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1,410 results on '"RNA interference"'

1. SALL4 promotes glycolysis and chromatin remodeling via modulating HP1α-Glut1 pathway

Author

Kim, J, Xu, S, Xiong, L, Yu, L, Fu, X, and Xu, Y

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Cancer, Genetics, Blotting, Western, Cell Line, Tumor, Chromatin Assembly and Disassembly, Chromobox Protein Homolog 5, Chromosomal Proteins, Non-Histone, Cullin Proteins, DNA Damage, DNA Repair, Glucose Transporter Type 1, Glycolysis, HEK293 Cells, Hep G2 Cells, History, 18th Century, Humans, Microscopy, Confocal, Neoplasms, RNA Interference, Signal Transduction, Transcription Factors, Clinical Sciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

SALL4 has recently been identified to promote chemo-resistance in multiple types of cancer, but the underlying mechanism remains to be fully established. Open chromatin structure is important for DNA damage response (DDR) and DNA repair. Here, we demonstrate that SALL4 promotes open chromatin by destabilizing heterochromatin protein 1α (HP1α) by recruiting ubiquitin E3 ligase CUL4B to HP1α. The silencing of SALL4 in cancer cells decreased the expression levels of Glut1 and inhibited glycolysis in cancer cells. The upregulation of HP1α in human cancer cells suppressed open chromatin, glycolysis and Glut1 expression levels. Therefore, SALL4 promotes the expression of Glut1 and open chromatin through a HP1α-dependent mechanism. Impaired DDR in SALL4-deficient human cancer cells can be rescued by the restored expression of Glut1, indicating the importance of HP1α-Glut1 axis in SALL4-mediated DDR. These findings demonstrate that SALL4 could induce drug resistance by enhancing DDR and DNA repair through promoting glycolysis and subsequent chromatin remodeling.

Published
2017

2. TGF-β signaling links E-cadherin loss to suppression of nucleotide excision repair

Author

Qiang, L, Shah, P, Barcellos-Hoff, MH, and He, YY

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Climate-Related Exposures and Conditions, Cancer, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Base Sequence, Blotting, Western, Cadherins, Cell Line, Cells, Cultured, DNA Damage, DNA Repair, DNA-Binding Proteins, Female, HEK293 Cells, Humans, Keratinocytes, Mice, Hairless, Microscopy, Fluorescence, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Nucleic Acid, Signal Transduction, Transforming Growth Factor beta, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

E-cadherin is a cell adhesion molecule best known for its function in suppressing tumor progression and metastasis. Here we show that E-cadherin promotes nucleotide excision repair through positively regulating the expression of xeroderma pigmentosum complementation group C (XPC) and DNA damage-binding protein 1 (DDB1). Loss of E-cadherin activates the E2F4 and p130/107 transcription repressor complexes to suppress the transcription of both XPC and DDB1 through activating the transforming growth factor-β (TGF-β) pathway. Adding XPC or DDB1, or inhibiting the TGF-β pathway, increases the repair of ultraviolet (UV)-induced DNA damage in E-cadherin-inhibited cells. In the mouse skin and skin tumors, UVB radiation downregulates E-cadherin. In sun-associated premalignant and malignant skin neoplasia, E-cadherin is downregulated in association with reduced XPC and DDB1 levels. These findings demonstrate a crucial role of E-cadherin in efficient DNA repair of UV-induced DNA damage, identify a new link between epithelial adhesion and DNA repair and suggest a mechanistic link of early E-cadherin loss in tumor initiation.

Published
2016

3. Runx1 contributes to neurofibromatosis type 1 neurofibroma formation.

Author

Li, H, Zhao, X, Yan, X, Jessen, W, Kim, M-O, Dombi, E, Liu, P, Huang, G, and Wu, J

Subjects
Animals, CCAAT-Binding Factor, Carrier Proteins, Cell Line, Tumor, Cell Transformation, Neoplastic, Core Binding Factor Alpha 2 Subunit, Fatty Acid-Binding Protein 7, Humans, Mice, Neurofibroma, Neurofibroma, Plexiform, Neurofibromatosis 1, Neurofibromin 1, RNA Interference, RNA, Small Interfering, Schwann Cells, Stem Cells, Tumor Suppressor Proteins
Abstract

Neurofibromatosis type 1 (NF1) patients are predisposed to neurofibromas but the driver(s) that contribute to neurofibroma formation are not fully understood. By cross comparison of microarray gene lists on human neurofibroma-initiating cells and developed neurofibroma Schwann cells (SCs) we identified RUNX1 overexpression in human neurofibroma initiation cells, suggesting RUNX1 might relate to neurofibroma formation. Immunostaining confirmed RUNX1 protein overexpression in human plexiform neurofibromas. Runx1 overexpression was confirmed in mouse Schwann cell progenitors (SCPs) and mouse neurofibromas at the messenger RNA and protein levels. Genetic inhibition of Runx1 expression by small hairpin RNA or pharmacological inhibition of Runx1 function by a Runx1/Cbfβ interaction inhibitor, Ro5-3335, decreased mouse neurofibroma sphere number in vitro. Targeted genetic deletion of Runx1 in SCs and SCPs delayed mouse neurofibroma formation in vivo. Mechanistically, loss of Nf1 increased embryonic day 12.5 Runx1(+)/Blbp(+) progenitors that enable tumor formation. These results suggest that Runx1 has an important role in Nf1 neurofibroma initiation, and inhibition of RUNX1 function might provide a novel potential therapeutic treatment strategy for neurofibroma patients.

Published
2016

4. Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis

Author

Zhou, JZ, Riquelme, MA, Gao, X, Ellies, LG, Sun, LZ, and Jiang, JX

Subjects
Cancer, Biotechnology, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Adenosine, Adenosine Triphosphate, Alendronate, Animals, Apyrase, Bone Density Conservation Agents, Bone Neoplasms, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cell Proliferation, Female, Humans, Mice, Mice, Inbred C57BL, Mice, Nude, Neoplasm Transplantation, Osteocytes, RNA Interference, RNA, Small Interfering, Receptor, Adenosine A2A, Receptors, Purinergic P2X, Signal Transduction, Transplantation, Heterologous, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Extracellular ATP has been shown to either inhibit or promote cancer growth and migration; however, the mechanism underlying this discrepancy remained elusive. Here we demonstrate the divergent roles of ATP and adenosine released by bone osteocytes on breast cancers. We showed that conditioned media (CM) collected from osteocytes treated with alendronate (AD), a bisphosphonate drug, inhibited the migration of human breast cancer MDA-MB-231 cells. Removal of the extracellular ATP by apyrase in CM abolished this effect, suggesting the involvement of ATP. ATP exerted its inhibitory effect through the activation of purinergic P2X receptor signaling in breast cancer cells evidenced by the attenuation of the inhibition by an antagonist, oxidized ATP, as well as knocking down P2X7 with small interfering RNA (siRNA), and the inhibition of migration by an agonist, BzATP. Intriguingly, ATP had a biphasic effect on breast cancer cells-lower dosage inhibited but higher dosage promoted its migration. The stimulatory effect on migration was blocked by an adenosine receptor antagonist, MRS1754, ARL67156, an ecto-ATPase inhibitor, and A2A receptor siRNA, suggesting that in contrast to ATP, adenosine, a metabolic product of ATP, promoted migration of breast cancer cells. Consistently, non-hydrolyzable ATP, ATPγS, only inhibited but did not promote cancer cell migration. ATP also had a similar inhibitory effect on the Py8119 mouse mammary carcinoma cells; however, adenosine had no effect owing to the absence of the A2A receptor. Consistently, ATPγS inhibited, whereas adenosine promoted anchorage-independent growth of MDA-MB-231 cells. Our in vivo xenograft study showed a significant delay of tumor growth with the treatment of ATPγS. Moreover, the extent of bone metastasis in a mouse intratibial model was significantly reduced with the treatment of ATPγS. Together, our results suggest the distinct roles of ATP and adenosine released by osteocytes and the activation of corresponding receptors P2X7 and A2A signaling on breast cancer cell growth, migration and bone metastasis.

Published
2015

5. Targeting Gli transcription activation by small molecule suppresses tumor growth.

Author

Bosco-Clément, G, Zhang, F, Chen, Z, Zhou, H-M, Li, H, Mikami, I, Hirata, T, Yagui-Beltran, A, Lui, N, Do, H, Cheng, T, Tseng, H-H, Choi, H, Fang, L-T, Kim, I-J, Yue, D, Wang, C, Zheng, Q, Fujii, N, He, B, Jablons, David, and Mann, Michael

Subjects
Animals, Cell Line, Tumor, Cell Proliferation, Female, HCT116 Cells, HEK293 Cells, HT29 Cells, Hedgehog Proteins, Humans, Immunoblotting, Mice, Mice, Nude, NIH 3T3 Cells, Neoplasms, Oligonucleotide Array Sequence Analysis, Protein Binding, Pyrazoles, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Small Molecule Libraries, TATA-Binding Protein Associated Factors, Transcription Factor TFIID, Transcription Factors, Transcriptional Activation, Transcriptome, Tumor Burden, Xenograft Model Antitumor Assays, Zinc Finger Protein GLI1
Abstract

Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study, we identified an interaction between Gli proteins and a transcription coactivator TBP-associated factor 9 (TAF9), and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and downregulate Gli/TAF9-dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy.

Published
2014

6. Chromatin effector Pygo2 regulates mammary tumor initiation and heterogeneity in MMTV-Wnt1 mice

Author

Watanabe, K, Fallahi, M, and Dai, X

Subjects
Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Cancer, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Animals, Anthelmintics, Cell Transformation, Neoplastic, Chromatin, Female, Genetic Variation, Intracellular Signaling Peptides and Proteins, Male, Mammary Glands, Animal, Mammary Neoplasms, Animal, Mammary Tumor Virus, Mouse, Mice, Mice, Transgenic, Neoplastic Stem Cells, Pyrvinium Compounds, RNA Interference, RNA, Small Interfering, Tumor Cells, Cultured, Wnt Signaling Pathway, Wnt1 Protein, MMTV-Wnt1, pygopus 2, Pygo2, mammary gland, tumor heterogeneity, cancer stem cells, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Little is known about chromatin mechanisms that regulate tumor-initiating cells that are proposed to be responsible for tumor recurrence and relapse. We have previously shown that Pygopus 2 (Pygo2), a chromatin effector and context-dependent Wnt signaling coactivator, regulates mammary gland development by expanding epithelial stem/progenitor cells. However, the role of Pygo2 in mammary tumorigenesis in vivo remains to be addressed. In this study, we show that epithelia-specific ablation of Pygo2 in MMTV-Wnt1 transgenic mice results in delayed mammary ductal elongation, but the hyperbranching phenotype, aberrant accumulation of stem/progenitor-like cells, and canonical Wnt signaling output are largely unaffected. Chronic loss of Pygo2 significantly delays mammary tumor onset in MMTV-Wnt1 females, whereas acute deletion of Pygo2 in MMTV-Wnt1 tumor cells leads to a significant decrease in their tumor-initiating capability upon transplantation. Finally, we provide evidence supporting a role for Pygo2 in modulating the lineage potential of MMTV-Wnt1 tumor initiating cells. Collectively, our results suggest that Pygo2 acts at a step downstream of mammary stem cell accumulation to facilitate transformation, and that it regulates the tumor initiating capacity and lineage preference of the already transformed mammary cells, in MMTV-Wnt1 mice. These findings offer valuable insights into our understanding of the molecular basis of heterogeneity within breast tumors.

Published
2014

7. A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer

Author

Ratner, ES, Keane, FK, Lindner, R, Tassi, RA, Paranjape, T, Glasgow, M, Nallur, S, Deng, Y, Lu, L, Steele, L, Sand, S, Muller, R-U, Bignotti, E, Bellone, S, Boeke, M, Yao, X, Pecorelli, S, Ravaggi, A, Katsaros, D, Zelterman, D, Cristea, MC, Yu, H, Rutherford, TJ, Weitzel, JN, Neuhausen, SL, Schwartz, PE, Slack, FJ, Santin, AD, and Weidhaas, JB

Subjects
Ovarian Cancer, Genetics, Rare Diseases, Clinical Research, Cancer, 2.1 Biological and endogenous factors, Aetiology, 3' Untranslated Regions, Aged, Antineoplastic Combined Chemotherapy Protocols, BRCA1 Protein, BRCA2 Protein, Biomarkers, Tumor, Carboplatin, Cell Line, Tumor, Cell Survival, Drug Resistance, Neoplasm, Female, Genotype, Humans, Kaplan-Meier Estimate, Middle Aged, Multivariate Analysis, Mutation, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Paclitaxel, Polymorphism, Single Nucleotide, Prognosis, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), RNA Interference, Treatment Outcome, ras Proteins, platinum resistance, KRAS variant, ovarian cancer, outcome, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Germline variants in the 3' untranslated region (3'UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3'UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125) and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio=1.67, 95% confidence interval: 1.09-2.57, P=0.019, n=279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio=3.18, confidence interval: 1.31-7.72, P=0.0106, n=291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro. These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3'UTR lesions, and that direct targeting may be a viable future treatment approach.

Published
2012

8. Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis

Author

Lemjabbar-Alaoui, H, van Zante, A, Singer, MS, Xue, Q, Wang, Y-Q, Tsay, D, He, B, Jablons, DM, and Rosen, SD

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Rare Diseases, Lung, Cancer, Tobacco, Tobacco Smoke and Health, Lung Cancer, 2.1 Biological and endogenous factors, Aetiology, Animals, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Transformation, Neoplastic, Data Mining, Gene Expression, Humans, Immunoblotting, Immunohistochemistry, Lung Neoplasms, Male, Mice, Mice, Nude, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Sulfatases, Sulfotransferases, Wnt Proteins, Xenograft Model Antitumor Assays, lung cancer, Sulf-2, sulfatase, heparan sulfate proteoglycans, Clinical Sciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Heparan sulfate (HS) proteoglycans (HSPGs) bind to multiple growth factors/morphogens and regulate their signaling. 6-O-sulfation (6S) of glucosamine within HS chains is critical for many of these ligand interactions. Sulf-1 and Sulf-2, which are extracellular neutral-pH sulfatases, provide a novel post-synthetic mechanism for regulation of HSPG function by removing 6S from intact HS chains. The Sulfs can thereby modulate several signaling pathways, including the promotion of Wnt signaling. We found induction of SULF2 transcripts and Sulf-2 protein in human lung adenocarcinoma and squamous cell carcinoma, the two major classes of non-small-cell lung carcinomas (NSCLCs). We confirmed widespread Sulf-2 protein expression in tumor cells of 10/10 surgical specimens of human lung squamous carcinomas. We studied five Sulf-2(+) NSCLC cell lines, including two, which were derived by cigarette-smoke transformation of bronchial epithelial cells. shRNA-mediated Sulf-2 knockdown in these lines caused an increase in 6S on their cell surface and in parallel reversed their transformed phenotype in vitro, eliminated autocrine Wnt signaling and strongly blunted xenograft tumor formation in nude mice. Conversely, forced Sulf-2 expression in non-malignant bronchial epithelial cells produced a partially transformed phenotype. Our findings support an essential role for Sulf-2 in lung cancer, the leading cancer killer.

Published
2010

9. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors

Author

Chitale, D, Gong, Y, Taylor, BS, Broderick, S, Brennan, C, Somwar, R, Golas, B, Wang, L, Motoi, N, Szoke, J, Reinersman, JM, Major, J, Sander, C, Seshan, VE, Zakowski, MF, Rusch, V, Pao, W, Gerald, W, and Ladanyi, M

Subjects
Biotechnology, Lung Cancer, Rare Diseases, Genetics, Human Genome, Lung, Cancer, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Cell Line, Tumor, Cell Proliferation, Chromosome Aberrations, Cluster Analysis, Cyclin-Dependent Kinase Inhibitor p16, Dual-Specificity Phosphatases, ErbB Receptors, Female, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, ras, Genome-Wide Association Study, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Lung Neoplasms, Male, Mitogen-Activated Protein Kinase Phosphatases, Mutation, Nucleic Acid Hybridization, RNA Interference, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers.

Published
2009

10. ZEB2 facilitates peritoneal metastasis by regulating the invasiveness and tumorigenesis of cancer stem-like cells in high-grade serous ovarian cancers

Author

Hua Jiang, Qiwang Lin, Ming Li, Yiying Li, Ying Qu, Yanan You, Yan Yuan, Pengfei Li, Fan Liang, He Fei, Tong Chen, and Mengyao Wu

Subjects
0301 basic medicine, Homeobox protein NANOG, Cancer Research, endocrine system diseases, Fluorescent Antibody Technique, Gene Expression, Vimentin, Kaplan-Meier Estimate, Biology, medicine.disease_cause, Models, Biological, Article, Immunophenotyping, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Ovarian cancer, Genetics, medicine, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Molecular Biology, Peritoneal Neoplasms, Proportional Hazards Models, Zinc Finger E-box Binding Homeobox 2, Ovarian Neoplasms, Gene knockdown, Cancer stem cells, Mesenchymal stem cell, Cancer, Prognosis, medicine.disease, Cystadenocarcinoma, Serous, Gene Expression Regulation, Neoplastic, MicroRNAs, Serous fluid, Cell Transformation, Neoplastic, 030104 developmental biology, ROC Curve, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Cancer research, biology.protein, Female, RNA Interference, Carcinogenesis, Biomarkers
Abstract

Abstract Peritoneal metastasis is a common issue in the progression of high-grade serous ovarian cancers (HGSOCs), yet the underlying mechanism remains unconfirmed. We demonstrated that ZEB2, the transcription factor of epithelial–mesenchymal transition (EMT), was upregulated in ascites cells from HGSOC patients and in CD133+ cancer stem-like cells (CSLCs) from epithelial ovarian cancer (EOC) cell lines. SiRNA-mediated knockdown of ZEB2 in EOC cells decreased the percentage of CSLCs and reduced the colony forming potential, cell invasion capacity and expression of pluripotent genes Oct4 and Nanog. Inhibition of ZEB2 also induced cellular apoptosis and impacted the tumorigenicity of ovarian CSLCs. The mesenchymal markers N-cadherin and vimentin were downregulated, while the epithelial marker E-cadherin was upregulated after ZEB2 knockdown. MiR-200a, a molecule that downregulates ZEB2, had the opposite effect of ZEB2 expression in EOC-CSLCs. A retrospective study of 98 HGSOC patients on the relationship of ascites volume, pelvic and abdominal metastasis, International Federation of Gynecology and Obstetrics (FIGO) stage and the malignant involvement of abdominal organs and lymph nodes was performed. Patients with high expression of ZEB2 in tumour tissues had a higher metastasis rate and a poorer prognosis than those with low expression. The parameters of ZEB2 expression and ascites volume were strongly linked with the prognostic outcome of HGSOC patients and had higher hazard ratios. These findings illustrated that ZEB2 facilitates the invasive metastasis of EOC-CSLCs and can predict peritoneal metastasis and a poor prognosis in HGSOC patients.

Published
2021

11. A novel homeostatic loop of sorcin drives paclitaxel-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human ovarian cancer

Author

Zhang, Jinguo, Guan, Wencai, Xu, Xiaolin, Wang, Fanchen, Li, Xin, and Xu, Guoxiong

Subjects
0301 basic medicine, Untranslated region, Cancer Research, Epithelial-Mesenchymal Transition, Paclitaxel, Gene Expression, Biology, Predictive markers, Models, Biological, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Western blot, Ovarian cancer, Cell Movement, Transcription (biology), Cell Line, Tumor, parasitic diseases, Biomarkers, Tumor, Genetics, medicine, Humans, Molecular Biology, Transcription factor, Cell Proliferation, Smad4 Protein, Ovarian Neoplasms, medicine.diagnostic_test, Calcium-Binding Proteins, Zinc Finger E-box-Binding Homeobox 1, Cancer, Promoter, social sciences, Prognosis, medicine.disease, MicroRNAs, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Cancer research, Female, RNA Interference, geographic locations
Abstract

The primary chemotherapy of ovarian cancer (OC) often acquires chemoresistance. Sorcin (SRI), a soluble resistance-related calcium-binding protein, has been reported to be an oncogenic protein in cancer. However, the molecular mechanisms of SRI regulation and the role and aberrant expression of SRI in chemoresistant OC remain unclear. Here, we identified SRI as a key driver of paclitaxel (PTX)-resistance and explored its regulatory mechanism. Using transcriptome profiles, qRT-PCR, proteomics, Western blot, immunohistochemistry, and bioinformatics analyses, we found that SRI was overexpressed in PTX-resistant OC cells and the overexpression of SRI was related to the poor prognosis of patients. SRI was a key molecule required for growth, migration, and PTX-resistance in vitro and in vivo and was involved in epithelial–mesenchymal transition (EMT) and stemness. Mechanistic studies showed that miR-142-5p directly bound to the 3ʹ-UTR of SRI to suppress its expression, whereas a transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) inhibited the transcription of miR-142-5p by directly binding to the E-box fragment in the miR-142 promoter region. Furthermore, ZEB1 was negatively regulated by SRI which physically interacted with Smad4 to block its translocation from the cytosol to the nucleus. Taken together, our findings unveil a novel homeostatic loop of SRI that drives the PTX-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human OC. Targeting this SRI/Smad4/ZEB1/miR-142-5p loop may reverse the PTX-resistance.

Published
2021

12. NF-κB-activated SPRY4-IT1 promotes cancer cell metastasis by downregulating TCEB1 mRNA via Staufen1-mediated mRNA decay

Author

Ming Zhang, Minjie Wei, Qiang Zhang, Longyang Jiang, Miao He, Lin Zhao, Qiutong Guan, Yalun Li, and Jingdong Zhang

Subjects
0301 basic medicine, Untranslated region, Cell biology, Cancer Research, RNA Stability, Elongin, Biology, Article, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Alu Elements, Cell Line, Tumor, Neoplasms, microRNA, Genetics, medicine, Humans, Neoplasm Metastasis, 3' Untranslated Regions, Molecular Biology, Cancer, Neoplasm Staging, Messenger RNA, Binding Sites, Competing endogenous RNA, NF-kappa B, RNA-Binding Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Cytoskeletal Proteins, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, RNA Interference, RNA, Long Noncoding, Ovarian cancer, Signal Transduction
Abstract

Previous study demonstrated that most long non-coding RNAs (lncRNAs) function as competing endogenous RNAs or molecular sponges to negatively modulate miRNA and regulate tumor development. However, the molecular mechanisms of lncRNAs in cancer are not fully understood. Our study describes the role of the lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) in cancer metastasis by mechanisms related to Staufen1 (STAU1)-mediated mRNA decay (SMD). Briefly, we found that, high SPRY4-IT1 expression was associated with aggressiveness and poor outcome in human colorectal, breast and ovarian cancer tissues. In addition, functional assays revealed that SPRY4-IT1 significantly promoted colorectal, breast and ovarian cancer metastasis in vitro and in vivo. Mechanistically, microarray analyses identified several differentially-expressed genes upon SPRY4-IT1 overexpression in HCT 116 colorectal cancer cells. Among them, the 3′-UTR of transcription elongation factor B subunit 1 (TCEB1) mRNA can base-pair with the Alu element in the 3′-UTR of SPRY4-IT1. Moreover, SPRY4-IT1 was found to bind STAU1, promote STAU1 recruitment to the 3′-UTR of TCEB1 mRNA, and affect TCEB1 mRNA stability and expression, resulting in hypoxia-inducible factor 1α (HIF-1α) upregulation, and thereby affecting cancer cell metastasis. In addition, STAU1 depletion abrogated TCEB1 SMD and alleviated the pro-metastatic effect of SPRY4-IT1 overexpression. Significantly, we revealed that SPRY4-IT1 is also transactivated by NF-κB/p65, which activates SPRY4-IT1 to inhibit TCEB1 expression, and subsequently upregulate HIF-1α. In conclusion, our results highlight a novel mechanism of cytoplasmic lncRNA SPRY4-IT1 in which SPRY4-IT1 affecting TCEB1 mRNA stability via STAU1-mediated degradation during cancer metastasis.

Published
2021

13. ZnT7 RNAi favors RafGOFscrib−/−-induced tumor growth and invasion in Drosophila through JNK signaling pathway

Author

Tian Wei, Yan Gao, Guiran Xiao, Xiaowen Ji, and Xiaomei Zhu

Subjects
0301 basic medicine, Cancer Research, biology, Kinase, Autophagy, Golgi apparatus, biology.organism_classification, medicine.disease, Cell biology, 03 medical and health sciences, symbols.namesake, 030104 developmental biology, 0302 clinical medicine, RNA interference, 030220 oncology & carcinogenesis, Genetics, Unfolded protein response, symbols, Zinc deficiency, medicine, Gene silencing, Drosophila melanogaster, Molecular Biology
Abstract

The disruption of zinc homeostasis has been identified in patients suffering from various cancers, but a causative relationship has not yet been established. Drosophila melanogaster has become a powerful model to study cancer biology. Here using a Drosophila model of malignant tumor RafGOFscrib-/-, we observed that the tumor growth, invasion and migration were enhanced by silencing dZnT7, a zinc transporter localized on the Golgi apparatus. Further study indicated that the zinc deficiency in Golgi of dZnT7 RNAi resulted in ER stress which could activate the c-Jun-N-terminal Kinase (JNK) signaling and this process is mediated by Atg9. Lastly, we demonstrated that the exacerbation of dZnT7 RNAi on tumor was promoted by JNK signaling-dependent cell autonomous and non-autonomous autophagy. These findings suggest that zinc homeostasis in secretory compartments may provide a new therapeutic target for tumor treatment.

Published
2021

14. Androgen receptor modulates metastatic routes of VHL wild-type clear cell renal cell carcinoma in an oxygen-dependent manner

Author

Qingbo Huang, Xu Zhang, Donglai Shen, Yuanjie Niu, Songliang Du, Chawnshang Chang, Wei Zhai, Chi-Ping Huang, Bosen You, Yin Sun, and Xin Ma

Subjects
0301 basic medicine, Cancer Research, biology, Wild type, urologic and male genital diseases, medicine.disease, female genital diseases and pregnancy complications, Metastasis, Androgen receptor, 03 medical and health sciences, Clear cell renal cell carcinoma, 030104 developmental biology, 0302 clinical medicine, Ubiquitin, Cell culture, RNA interference, 030220 oncology & carcinogenesis, Genetics, biology.protein, medicine, Cancer research, Receptor, Molecular Biology
Abstract

Recent studies indicated that the androgen receptor (AR) plays important roles in modulating metastasis of VHL-mutant clear cell renal cell carcinoma (ccRCC). However, the precise mechanisms of AR roles in VHL wild-type (VHL-wt) ccRCC, remain unclear. Here we found that AR interacted with VHL to modulate the metastasis of VHL-wt ccRCC via an oxygen-dependent manner. Mechanism dissection revealed that AR could transcriptionally suppress the miR-185-5p expression in the presence of functional VHL-wt protein under a normoxic condition, which might then result in increasing the expression of VEGF-A and VEGF-C via targeting the 3′UTR of mRNAs at a post-transcriptional level. In contrast, under a hypoxic condition, AR could increase miR-185-5p expression to suppress VEGF-C expression, yet this miR-185-5p effect on VEGF-A was reversed via AR’s positive regulation on the HIF2α-increased VEGF-A expression that resulted in increasing VEGF-A in the VHL-wt RCC cells. These distinct AR functions under different oxygen conditions may involve the VHL-impacted ubiquitination and nuclear localization of AR. The differential regulation of VEGF-A vs VEGF-C by AR may then result in differential impacts on the ccRCC metastatic destinations of VHL-wt ccRCC cells under different oxygen conditions. These finer mechanisms may help in the development of a novel therapy to better suppress the ccRCC progression under different oxygenization conditions.

Published
2020

15. Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth

Author

Nicolás Bellora, Franco Izzo, Rosalia Ines Cordo Russo, Pablo Guzmán, Juan Carlos Roa, Matías G. Pereyra, Mara De Martino, Mauro E. Cenciarini, Ezequiel Petrillo, Silvina Figurelli, Jose L. Daniotti, Daniel Lopez Della Vecchia, Osvaldo L. Podhajcer, Sabrina Barchuk, Lucía Santa María de la Parra, Patricia V. Elizalde, Violeta A. Chiauzzi, Cecilia J. Proietti, Leandro N. Guttlein, Roxana Schillaci, María F. Chervo, and Agustina Dupont

Subjects
0301 basic medicine, Gene isoform, Cancer Research, Receptor, ErbB-2, Otras Ciencias Biológicas, Triple Negative Breast Neoplasms, Receptor tyrosine kinase, Ciencias Biológicas, Transcriptome, 03 medical and health sciences, ErbB-2, Breast cancer, 0302 clinical medicine, ErbB, RNA interference, Cell Line, Tumor, Genetics, Humans, Protein Isoforms, Molecular Biology, Transcription factor, Mitogen-Activated Protein Kinase 7, Triple-negative breast cancer, Cell Proliferation, Cell Nucleus, Paraffin Embedding, biology, Alternative splicing, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, TNBC, CIENCIAS NATURALES Y EXACTAS
Abstract

Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2/HER2, a receptor tyrosine kinase. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Clinical biomarkers and targeted therapies for this disease remain elusive, so chemotherapy has been the standard of care for early and metastatic TNBC. Our present findings placed ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2). Our study on ErbB-2 alternative splicing events, using a PCR-sequencing approach combined with an RNA interference strategy, revealed that TNBC cells express either the canonical (wild-type) ErbB-2, encoded by transcript variant 1, or the non-canonical ErbB-2 isoform c, encoded by alternative variant 3 (RefSeq), or both. These ErbB-2 isoforms function in the nucleus as transcription factors. Evicting both from the nucleus or silencing isoform c only, blocks TN cell and tumor growth. This reveals not only NErbB-2 canonical and alternative isoforms role as targets of therapy in TNBC, but also isoform c dominant oncogenic potential. Furthermore, we validated our findings in the clinic and observed that NErbB-2 correlates with poor prognosis in primary TN tumors, disclosing NErbB-2 as a novel biomarker for TNBC. Our discoveries challenge the present scenario of drug development for personalized BC medicine that focuses on wild-type RefSeq proteins, which conserve the canonical domains and are located in their classical cellular compartments. Fil: Chervo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Cordo Russo, Rosalia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Petrillo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Izzo, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: de Martino, Mara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Bellora, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto Andino Patagónico de Tecnologías Biológicas y Geoambientales. Universidad Nacional del Comahue. Instituto Andino Patagónico de Tecnologías Biológicas y Geoambientales; Argentina Fil: Cenciarini, Mauro Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Chiauzzi, Violeta Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Santa María de la Parra, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Pereyra Matías G.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Güttlein, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Daniotti, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina Fil: Dupont, Agustina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Barchuk, Sabrina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Figurelli, Silvina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Lopez Della Vecchia, Daniel Edgardo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina Fil: Roa, Juan Carlos. Universidad de La Frontera. Núcleo Científico y Tecnológico en Recursos Naturales; Chile. Pontificia Universidad Católica de Chile; Chile Fil: Guzmán, Pablo. Universidad de La Frontera. Núcleo Científico y Tecnológico en Recursos Naturales; Chile Fil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Published
2020

16. AR-induced long non-coding RNA LINC01503 facilitates proliferation and metastasis via the SFPQ-FOSL1 axis in nasopharyngeal carcinoma

Author

Ying-Qing Li, Ye-Lin Liang, Ying-Qin Li, Na Liu, Qian Li, Pan-Pan Zhang, Jun Ma, Jun-Yan Li, Shi-Wei He, Cheng Xu, Yin Zhao, Sheng-Yan Huang, Yuan Lei, and Yang Chen

Subjects
0301 basic medicine, Cancer Research, Biology, medicine.disease_cause, Article, Prognostic markers, 03 medical and health sciences, 0302 clinical medicine, RNA interference, otorhinolaryngologic diseases, Genetics, medicine, Cell migration, Head and neck cancer, Molecular Biology, Gene knockdown, medicine.disease, Long non-coding RNA, Androgen receptor, stomatognathic diseases, 030104 developmental biology, Nasopharyngeal carcinoma, 030220 oncology & carcinogenesis, Cancer research, Ectopic expression, Carcinogenesis
Abstract

Increasing evidence indicates that long non-coding RNAs (lncRNAs) play vital roles in the tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in nasopharyngeal carcinoma (NPC) are still largely unknown. Our previous lncRNA expression profiles identified that LINC01503 was overexpressed in NPC. Here, we verified that LINC01503 was highly expressed in NPC and correlated with poor prognosis. LINC01503 promoted NPC cell proliferation, migration, and invasion in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, LINC01503 recruited splicing factor proline-and glutamine-rich (SFPQ) to activate Fos like 1 (FOSL1) transcription, and ectopic expression of FOSL1 reversed the suppressive effect of LINC01503 knockdown on NPC progression. Moreover, androgen receptor (AR)-mediated transcription activation was responsible for the overexpression of LINC01503, and AR ligand-dependent cell growth, migration, and invasion in NPC cells. Taken together, our findings reveal that AR-induced LINC01503 can promote NPC progression through the SFPQ-FOSL1 axis, which represents a novel prognostic biomarker and therapeutic target for NPC patients.

Published
2020

17. Inhibiting Importin 4-mediated nuclear import of CEBPD enhances chemosensitivity by repression of PRKDC-driven DNA damage repair in cervical cancer

Author

Shuai Wang, Lili Zhu, Hongfang Shao, Li-Peng Hu, Zhigang Zhang, Bo Ni, Yincheng Teng, Miao Dai, Xiaolu Zhu, Bikang Yang, Qing Li, Xiao Li, Xueli Zhang, Qinyang Xu, Fei Liu, Yifei Shen, Yang Zhou, and Shu-Heng Jiang

Subjects
CCAAT-Enhancer-Binding Protein-delta, inorganic chemicals, 0301 basic medicine, Cancer Research, DNA Repair, DNA damage, Morpholines, Active Transport, Cell Nucleus, Mice, Nude, Uterine Cervical Neoplasms, Antineoplastic Agents, DNA-Activated Protein Kinase, Biology, Article, Small hairpin RNA, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, RNA interference, Cell Line, Tumor, Genetics, medicine, Animals, Humans, neoplasms, Molecular Biology, Cisplatin, Regulation of gene expression, Gene knockdown, Membrane Transport Proteins, Xenograft Model Antitumor Assays, female genital diseases and pregnancy complications, Gene Expression Regulation, Neoplastic, Cancer therapeutic resistance, 030104 developmental biology, Chromones, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cervical cancer, Cancer research, Female, RNA Interference, Nuclear localization sequence, DNA Damage, HeLa Cells, medicine.drug
Abstract

Cervical cancer (CC) remains highest in the mortality of female reproductive system cancers, while cisplatin (CDDP) resistance is the one of main reasons for the lethality. Preceding evidence has supported that karyopherins are associated with chemoresistance. In this study, we simultaneously compared CDDP-incomplete responders with CDDP-complete responders of CC patients and CDDP‐insensitive CC cell lines with CDDP‐sensitive group. We finally identified that DNA-PKcs (PRKDC) was related to CDDP sensitivity after overlapping in CC sample tissues and CC cell lines. Further functional assay revealed that targeting PRKDC by shRNA and NU7026 (specific PRKDC inhibitor) could enhance CDDP sensitivity in vitro and in vivo, which was mediated by impairing DNA damage repair pathway in CC. Mechanistically, we found that PRKDC was transcriptionally upregulated by CCAAT/enhancer-binding protein delta (CEBPD), while intriguingly, CDDP treatment strengthened the transcriptional activity of CEBPD to PRKDC. We further disclosed that Importin 4 (IPO4) augmented the nuclear translocation of CEBPD through nuclear localization signals (NLS) to activate PRKDC-mediated DNA damage repair in response to CDDP. Moreover, we demonstrated that IPO4 and CEBPD knockdown improved CDDP-induced cytotoxicity in vitro and in vivo. Together, we shed the novel insight into the role of IPO4 in chemosensitivity and provide a clinical translational potential to enhance CC chemosensitivity since the IPO4-CEBPD-PRKDC axis is actionable via NU7026 (PRKDC inhibitor) or targeting IPO4 in combination with CDDP.

Published
2020

18. The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis

Author

Jason Li, Lie Yang, Youfang Zhang, Pacman Szeto, Anthony T. Papenfuss, Aishwarya Kulkarni, Gamze Kuser Abali, Ramyar Molania, Catriona McLean, Mark Shackleton, Kaushalya C. Amarasinghe, Ismael A. Vergara, Xiaomeng Zhang, and Kieran F. Harvey

Subjects
0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Cancer Research, Lung Neoplasms, Skin Neoplasms, Cell, Mice, SCID, Protein Serine-Threonine Kinases, Biology, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Mice, Inbred NOD, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Hippo Signaling Pathway, Melanoma, neoplasms, Molecular Biology, Adaptor Proteins, Signal Transducing, Mice, Knockout, Hippo signaling pathway, Antibiotics, Antineoplastic, Gene Expression Profiling, YAP-Signaling Proteins, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, medicine.anatomical_structure, Doxorubicin, 030220 oncology & carcinogenesis, CYR61, Cutaneous melanoma, Cancer research, RNA Interference, Skin cancer, Signal Transduction, Transcription Factors
Abstract

Melanoma is a deadly form of skin cancer that accounts for a disproportionally large proportion of cancer-related deaths in younger people. Compared with most other skin cancers, a feature of melanoma is its high metastatic capacity, although the mechanisms that confer this are not well understood. The Hippo pathway is a key regulator of organ growth and cell fate that is deregulated in many cancers. To analyse the Hippo pathway in cutaneous melanoma, we generated a transcriptional signature of melanoma cells that overexpressed YAP, the key downstream Hippo pathway oncoprotein. YAP-mediated transcriptional activity varied in melanoma cell lines but did not cluster with known genetic drivers of melanomagenesis such as BRAF and NRAS mutations. Instead, it correlated strongly with published gene expression profiles linked to melanoma cell invasiveness and varied throughout the metastatic cascade in melanoma patient tumours. Consistent with this, YAP was both necessary and sufficient for melanoma cell invasion in vitro. In vivo, YAP promoted spontaneous melanoma metastasis, whilst the growth of YAP-expressing primary tumours was impeded. Finally, we identified the YAP target genes AXL, THBS1 and CYR61 as key mediators of YAP-induced melanoma cell invasion. These data suggest that YAP is a critical regulator of melanoma metastasis.

Published
2020

19. S100A14 suppresses metastasis of nasopharyngeal carcinoma by inhibition of NF-kB signaling through degradation of IRAK1

Author

Si-Ting Lin, Li-Xia Peng, Dong-Fang Meng, Yan Mei, Guo-Ying Liu, Rui Sun, Bi-Jun Huang, Yan-Hong Lang, Li-Sheng Zheng, Xing-Tang Niu, Chang-Zhi Li, Hao Hu, Hai-Feng Li, Di-Tian Shu, Ling-Ling Guo, De-Huan Xie, Fei-Fei Luo, Chao-Nan Qian, Liang Xu, Yuan-Yuan Qiang, Ping Xie, Zhi-Jie Liu, Xing-Si Peng, and Ming-Dian Wang

Subjects
0301 basic medicine, Proteasome Endopeptidase Complex, Cancer Research, Epithelial-Mesenchymal Transition, Lung Neoplasms, Mice, Nude, Motility, Biology, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, otorhinolaryngologic diseases, Genetics, medicine, Animals, Humans, Molecular Biology, Feedback, Physiological, Nasopharyngeal Carcinoma, Kinase, Calcium-Binding Proteins, NF-kappa B, Nasopharyngeal Neoplasms, IRAK1, Cell migration, medicine.disease, Survival Analysis, Gene Expression Regulation, Neoplastic, stomatognathic diseases, Interleukin-1 Receptor-Associated Kinases, 030104 developmental biology, Nasopharyngeal carcinoma, 030220 oncology & carcinogenesis, Cancer research, Heterografts, Immunohistochemistry, RNA Interference, Signal transduction, Signal Transduction
Abstract

Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with highly aggressive and metastatic potential in which distant metastasis is the main reason for treatment failure. Till present, the underlying molecular mechanisms of NPC metastasis remains poorly understood. Here, we identified S100 calcium-binding protein A14 (S100A14) as a functional regulator suppressing NPC metastasis by inhibiting the NF-kB signaling pathway and reversing the epithelial-mesenchymal transition (EMT). S100A14 was found to be downregulated in highly metastatic NPC cells and tissues. Immunohistochemical staining of 202 NPC samples revealed that lower S100A14 expression was significantly correlated with shorter patient overall survival (OS) and distant metastasis-free survival (DMFS). S100A14 was also found as an independent prognostic factor for favorable survival. Gain- and loss-of-function studies confirmed that S100A14 suppressed the in vitro and in vivo motility of NPC cells. Mechanistically, S100A14 promoted the ubiquitin-proteasome-mediated degradation of interleukin-1 receptor-associated kinase 1 (IRAK1) to suppress NPC cellular migration. Moreover, S100A14 and IRAK1 established a feedback loop that could be disrupted by the IRAK1 inhibitor T2457. Overall, our findings showed that the S100A14-IRAK1 feedback loop could be a promising therapeutic target for NPC metastasis.

Published
2020

20. Histone chaperone FACT is essential to overcome replication stress in mammalian cells

Author

Erin Hong, Laura Prendergast, Alfiya Safina, Katerina Gurova, and Dante Poe

Subjects
DNA Replication, 0301 basic medicine, Cancer Research, Programmed cell death, DNA damage, DNA, Single-Stranded, Ataxia Telangiectasia Mutated Proteins, Biology, Article, Cell Line, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Replication Protein A, Genetics, Animals, Humans, Histone Chaperones, Molecular Biology, Cells, Cultured, Mice, Knockout, Gene knockdown, Minichromosome Maintenance Proteins, High Mobility Group Proteins, DNA replication, Helicase, Chromatin, Cell biology, DNA-Binding Proteins, 030104 developmental biology, Histone, 030220 oncology & carcinogenesis, Chaperone (protein), Checkpoint Kinase 1, MCF-7 Cells, biology.protein, RNA Interference, Transcriptional Elongation Factors, DNA Damage
Abstract

The histone chaperone FACT is upregulated during mammary tumorigenesis and necessary for the viability and growth of breast tumor cells. We established that only proliferating tumor cells are sensitive to FACT knockdown, suggesting that FACT functions during DNA replication in tumor cells but not in normal cells. We hypothesized that the basal level of replication stress defines the FACT dependence of cells. Using genetic and chemical tools, we demonstrated that FACT is needed to overcome replication stress. In the absence of FACT during replication stress, the MCM2-7 helicase dissociates from chromatin, resulting in the absence of ssDNA accumulation, RPA binding, and activation of the ATR/CHK1 checkpoint response. Without this response, stalled replication forks are not stabilized, and new origin firing cannot be prevented, leading to the accumulation of DNA damage and cell death. Thus, we propose a novel role for FACT as a factor preventing helicase dissociation from chromatin during replication stress.

Published
2020

21. GBP2 enhances glioblastoma invasion through Stat3/fibronectin pathway

Author

Xiaoting Yu, Lili Sun, Qing Lan, Shuye Yu, Clark C. Chen, Hui Xu, Ming Li, Lili Chen, Jing Jin, and Yanwen Zheng

Subjects
0301 basic medicine, Cancer Research, GBP2, Cell migration, Biology, Fibronectin, Transplantation, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, RNA interference, 030220 oncology & carcinogenesis, Genetics, biology.protein, Cancer research, Gene silencing, Signal transduction, STAT3, Molecular Biology
Abstract

Guanylate-binding protein 2 (GBP2) is an interferon-inducible large GTPase which is crucial to the protective immunity against microorganisms. However, its biological function in cancer remains largely unknown. Glioblastoma multiforme (GBM) is the most common and deadly brain tumor in adults. Here we show that GBP2 expression is highly elevated in GBM tumor and cell lines, particularly in those of the mesenchymal subtype. High GBP2 expression is associated with poor prognosis. GBP2 overexpression significantly promotes GBM cell migration and invasion in vitro, and GBP2 silencing by RNA interference exhibits opposite effects. We further show that fibronectin (FN1) is dramatically induced by GBP2 expression at both mRNA and protein levels, and FN1 is essential for GBP2-promoted GBM invasiveness. Inhibition of Stat3 pathway prevents GBP2-promoted FN1 induction and cell invasion. Consistently, GBP2 dramatically promotes GBM tumor growth and invasion in mice and significantly reduces the survival time of the mice with tumor. Taken together, these findings establish the role of GBP2/Stat3/FN1 signaling cascade in GBM invasion and suggest GBP2 may serve as a potential therapeutic target for inhibiting GBM invasion.

Published
2020

22. ZSCAN4 facilitates chromatin remodeling and promotes the cancer stem cell phenotype

Author

Michal Arad, Rodney J. Taylor, Kristen H Angster, W. Alex Meltzer, Michal Zalzman, Robert A. Brown, Benjamin A. Portney, Andrea Hebert, Aditi Gupta, Lorna E. Silipino, Phyo Nay Lin, and Raju Khatri

Subjects
0301 basic medicine, Homeobox protein NANOG, Cancer Research, Chromatin remodelling, Mice, SCID, Article, Chromatin remodeling, Histones, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Mice, Inbred NOD, Cancer stem cell, Target identification, Cell Line, Tumor, Genetics, Animals, Humans, Molecular Biology, Mice, Knockout, biology, Cancer stem cells, Acetylation, Nanog Homeobox Protein, Chromatin Assembly and Disassembly, Xenograft Model Antitumor Assays, Embryonic stem cell, Chromatin, Telomere, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Phenotype, 030104 developmental biology, Histone, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Neoplastic Stem Cells, biology.protein, Cancer research, RNA Interference, Octamer Transcription Factor-3, Transcription Factors
Abstract

Cancer stem cells (CSCs) are cells within tumors that maintain the ability to self-renew, drive tumor growth, and contribute to therapeutic resistance and cancer recurrence. In this study, we investigate the role of Zinc finger and SCAN domain containing 4 (ZSCAN4) in human head and neck squamous cell carcinoma (HNSCC). The murine Zscan4 is involved in telomere maintenance and genomic stability of mouse embryonic stem cells. Our data indicate that the human ZSCAN4 is enriched for, marks and is co-expressed with CSC markers in HNSCC. We show that transient ZSCAN4 induction for just 2 days increases CSC frequency both in vitro and in vivo and leads to upregulation of pluripotency and CSC factors. Importantly, we define for the first time the role of ZSCAN4 in altering the epigenetic profile and regulating the chromatin state. Our data show that ZSCAN4 leads to a functional histone 3 hyperacetylation at the promoters of OCT3/4 and NANOG, leading to an upregulation of CSC factors. Consistently, ZSCAN4 depletion leads to downregulation of CSC markers, decreased ability to form tumorspheres and severely affects tumor growth. Our study suggests that ZSCAN4 plays an important role in the maintenance of the CSC phenotype, indicating it is a potential therapeutic target in HNSCC.

Published
2020

23. The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma

Author

Michelle A. Lawson, Jennifer M. Down, Lisa J. Crawford, Dharminder Chauhan, Andrew D Chantry, Claudia Hamilton, Jonathan J. Morgan, Treen C. M. Morris, Krishnaraj Rajalingam, Alexandra E. Irvine, Roisin McAvera, Aswini Krishnan, and David Campbell

Subjects
0301 basic medicine, Cancer Research, Ubiquitylation, Cell Survival, Ubiquitin-Protein Ligases, Myeloma, Antineoplastic Agents, Bone Marrow Cells, Mice, SCID, Article, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Ubiquitin, Mice, Inbred NOD, Cell Line, Tumor, Genetics, medicine, Animals, Humans, RNA, Small Interfering, Molecular Biology, Lenalidomide, Cell Proliferation, Gene knockdown, biology, Oncogene, Cell growth, Tumor Suppressor Proteins, Ubiquitination, Cell Cycle Checkpoints, Ubiquitin ligase, Therapeutic Index, Drug, 030104 developmental biology, medicine.anatomical_structure, chemistry, Proteasome, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Female, RNA Interference, Bone marrow, Growth inhibition, Multiple Myeloma, Oligopeptides
Abstract

Proteasome inhibitors have provided a significant advance in the treatment of multiple myeloma (MM). Consequently, there is increasing interest in developing strategies to target E3 ligases, de-ubiquitinases, and/or ubiquitin receptors within the ubiquitin proteasome pathway, with an aim to achieve more specificity and reduced side-effects. Previous studies have shown a role for the E3 ligase HUWE1 in modulating c-MYC, an oncogene frequently dysregulated in MM. Here we investigated HUWE1 in MM. We identified elevated expression of HUWE1 in MM compared with normal cells. Small molecule-mediated inhibition of HUWE1 resulted in growth arrest of MM cell lines without significantly effecting the growth of normal bone marrow cells, suggesting a favorable therapeutic index. Studies using a HUWE1 knockdown model showed similar growth inhibition. HUWE1 expression positively correlated with MYC expression in MM bone marrow cells and correspondingly, genetic knockdown and biochemical inhibition of HUWE1 reduced MYC expression in MM cell lines. Proteomic identification of HUWE1 substrates revealed a strong association of HUWE1 with metabolic processes in MM cells. Intracellular glutamine levels are decreased in the absence of HUWE1 and may contribute to MYC degradation. Finally, HUWE1 depletion in combination with lenalidomide resulted in synergistic anti-MM activity in both in vitro and in vivo models. Taken together, our data demonstrate an important role of HUWE1 in MM cell growth and provides preclinical rationale for therapeutic strategies targeting HUWE1 in MM.

Published
2020

24. Functional genomics identifies new synergistic therapies for retinoblastoma

Author

Jeffrey L. Wrana, Joel Pearson, Tao Yu, Rod Bremner, Mohammad E. Ahmad, Madhavan Jagadeesan, Jason Moffat, Katherine Huang, Suying Lu, Troy Ketela, Vikas Khetan, Kevin R. Brown, Arthur Aubry, and Izhar Livne-Bar

Subjects
0301 basic medicine, Cancer Research, Cell cycle checkpoint, DNA damage, DNA repair, Biology, Article, Paediatric cancer, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Targeted therapies, RNA interference, Genetics, medicine, Chemotherapy, Animals, Humans, Molecular Biology, Navitoclax, Retinoblastoma, Genomics, medicine.disease, Pediatric cancer, Cancer therapeutic resistance, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, RNAi, Cancer research, Functional genomics
Abstract

Local intravitreal or intra-arterial chemotherapy has improved therapeutic success for the pediatric cancer retinoblastoma (RB), but toxicity remains a major caveat. RB initiates primarily withRB1loss or, rarely,MYCNamplification, but the critical downstream networks are incompletely understood. We set out to uncover perturbed molecular hubs, identify synergistic drug combinations to target these vulnerabilities, and expose and overcome drug resistance. We applied dynamic transcriptomic analysis to identify network hubs perturbed in RB versus normal fetal retina, and performed in vivo RNAi screens inRB1nullandRB1wt;MYCNamporthotopic xenografts to pinpoint essential hubs. We employed in vitro and in vivo studies to validate hits, define mechanism, develop new therapeutic modalities, and understand drug resistance. We identified BRCA1 and RAD51 as essential for RB cell survival. Their oncogenic activity was independent of BRCA1 functions in centrosome, heterochromatin, or ROS regulation, and instead linked to DNA repair. RAD51 depletion or inhibition with the small molecule inhibitor, B02, killed RB cells in a Chk1/Chk2/p53-dependent manner. B02 further synergized with clinically relevant topotecan (TPT) to engage this pathway, activating p53–BAX mediated killing of RB but not human retinal progenitor cells. Paradoxically, a B02/TPT-resistant tumor exhibited more DNA damage than sensitive RB cells. Resistance reflected dominance of the p53–p21 axis, which mediated cell cycle arrest instead of death. Deleting p21 or applying the BCL2/BCL2L1 inhibitor Navitoclax re-engaged the p53–BAX axis, and synergized with B02, TPT or both to override resistance. These data expose new synergistic therapies to trigger p53-induced killing in diverse RB subtypes.

Published
2020

25. HSP47 promotes metastasis of breast cancer by interacting with myosin IIA via the unfolded protein response transducer IRE1α

Author

Kenjiro Minomi, Akihiro Yoneda, and Yasuaki Tamura

Subjects
0301 basic medicine, Cancer Research, animal structures, Population, Mice, Nude, Breast Neoplasms, Protein Serine-Threonine Kinases, Malignancy, Metastasis, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Cell Line, Tumor, Endoribonucleases, Tumor Microenvironment, Genetics, medicine, Animals, Humans, Neoplasm Metastasis, RNA, Small Interfering, education, HSP47 Heat-Shock Proteins, Molecular Biology, Actin, Heat shock protein 47, Mice, Inbred BALB C, education.field_of_study, biology, Nonmuscle Myosin Type IIA, medicine.disease, Extracellular Matrix, 030104 developmental biology, 030220 oncology & carcinogenesis, Chaperone (protein), embryonic structures, Unfolded Protein Response, Unfolded protein response, biology.protein, Cancer research, Female, RNA Interference, Signal Transduction
Abstract

Breast cancer (BC) is an aggressive cancer that is a leading cause of cancer-associated death in women worldwide. Although increased expression of heat shock protein 47 (HSP47), a collagen-specific chaperone, is associated with the high malignancy of BC, its role in BC remains largely unclear. Here we show that a small population of high-invasive BC cells expresses HSP47 and that HSP47-positive high-invasive BC cells have a high metastatic potential that is completely abolished by disruption of HSP47. HSP47 interacts with non-muscle myosin IIA (NMIIA) via the unfolded protein response transducer IRE1α, resulting in enhancement of the metastatic potential of high-invasive BC cells by augmenting the contractile force of actin filaments. Ablation of NMIIA abrogates the metastatic potential of HSP47-positive high-invasive BC cells. We further show that forced expression of NMIIA confers a high metastatic potential on low-invasive BC cells in which HSP47 but not NMIIA is expressed. Overall, our study indicates that HSP47 acts as a stimulator for metastasis of BC cells and suggest that HSP47 may be a candidate for a therapeutic target against BC.

Published
2020

26. Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities

Author

Pancholi, Sunil, Ribas, Ricardo, Simigdala, Nikiana, Schuster, Eugene, Nikitorowicz-Buniak, Joanna, Ressa, Anna, Gao, Qiong, Leal, Mariana Ferreira, Bhamra, Amandeep, Thornhill, Allan, Morisset, Ludivine, Montaudon, Elodie, Sourd, Laura, Fitzpatrick, Martin, Altelaar, Maarten, Johnston, Stephen R, Marangoni, Elisabetta, Dowsett, Mitch, Martin, Lesley-Ann, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Afd Biomol.Mass Spect. and Proteomics, and Biomolecular Mass Spectrometry and Proteomics

Subjects
0301 basic medicine, MAPK/ERK pathway, Cancer Research, Fulvestrant/administration & dosage, Pyridines, Nude, Drug Resistance, Cyclin-Dependent Kinase 4/genetics, Drug Resistance, Neoplasm/drug effects, Retinoblastoma Protein, Piperazines, Tamoxifen/administration & dosage, Mice, Breast cancer, 0302 clinical medicine, Neoplasm/drug effects, Antineoplastic Combined Chemotherapy Protocols, Receptors, Kinome, Piperazines/pharmacology, Fulvestrant, Inbred BALB C, Pyridines/pharmacology, Mice, Inbred BALB C, Tumor, Cyclin-Dependent Kinase 6/genetics, biology, Receptors, Estrogen/genetics, Cell cycle, Wee1, Receptors, Estrogen, 030220 oncology & carcinogenesis, MCF-7 Cells, Female, RNA Interference, medicine.drug, Mice, Nude, Breast Neoplasms, Breast Neoplasms/genetics, Palbociclib, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Article, Cell Line, 03 medical and health sciences, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Cancer models, Protein Kinase Inhibitors, Molecular Biology, Retinoblastoma Protein/genetics, Cyclin-Dependent Kinase 4, Estrogen/genetics, Cyclin-Dependent Kinase 6, Xenograft Model Antitumor Assays, Tamoxifen, 030104 developmental biology, Xenograft Model Antitumor Assays/methods, Drug Resistance, Neoplasm, Protein Kinase Inhibitors/pharmacology, biology.protein, Cancer research, TSC2
Abstract

Combination of CDK4/6 inhibitors and endocrine therapy improves clinical outcome in advanced oestrogen receptor (ER)-positive breast cancer, however relapse is inevitable. Here, we show in model systems that other than loss ofRB1few gene-copy number (CN) alterations are associated with irreversible-resistance to endocrine therapy and subsequent secondary resistance to palbociclib. Resistance to palbociclib occurred as a result of tumour cell re-wiring leading to increased expression ofEGFR, MAPK, CDK4, CDK2, CDK7, CCNE1andCCNE2. Resistance altered the ER genome wide-binding pattern, leading to decreased expression of ‘classical’ oestrogen-regulated genes and was accompanied by reduced sensitivity to fulvestrant and tamoxifen. Persistent CDK4 blockade decreased phosphorylation of tuberous sclerosis complex 2 (TSC2) enhancing EGFR signalling, leading to the re-wiring of ER. Kinome-knockdown confirmed dependency on ERBB-signalling and G2/M–checkpoint proteins such as WEE1, together with the cell cycle master regulator, CDK7. Noteworthy, sensitivity to CDK7 inhibition was associated with loss of ER andRB1CN. Overall, we show that resistance to CDK4/6 inhibitors is dependent on kinase re-wiring and the redeployment of signalling cascades previously associated with endocrine resistance and highlights new therapeutic networks that can be exploited upon relapse after CDK4/6 inhibition.

Published
2020

27. AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis

Author

Ka Fai To, Jun Yu, Tingting Huang, Patrick Ming-Kuen Tang, Yuhang Zhou, Kwok Wai Lo, Jinglin Zhang, Liping Liu, Feng Wu, Chi Chun Wong, Nuoqing Weng, Nathalie Wong, Man Wu, Wei Kang, Alfred S. L. Cheng, and Hui Li

Subjects
0301 basic medicine, Cancer Research, Kaplan-Meier Estimate, medicine.disease_cause, Tumour biomarkers, Mice, 0302 clinical medicine, RNA, Small Interfering, Regulation of gene expression, YAP1, Recombinant Proteins, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Hippo signaling, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Heterografts, RNA Interference, Signal transduction, Protein Binding, Signal Transduction, Proteasome Endopeptidase Complex, Active Transport, Cell Nucleus, Antineoplastic Agents, Biology, Protein Serine-Threonine Kinases, Article, 03 medical and health sciences, Downregulation and upregulation, Stomach Neoplasms, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Hippo Signaling Pathway, Molecular Biology, Adaptor Proteins, Signal Transducing, Cell Nucleus, Protein transport, Connective Tissue Growth Factor, Membrane Proteins, Verteporfin, YAP-Signaling Proteins, Angiomotin, CTGF, 030104 developmental biology, Angiomotins, Cancer research, Carcinogenesis, Gastric cancer, Transcription Factors
Abstract

Hippo signaling functions to limit cellular growth, but the aberrant nuclear accumulation of its downstream YAP1 leads to carcinogenesis. YAP1/TEAD complex activates the oncogenic downstream transcription, such as CTGF and c-Myc. How YAP1 is protected in the cytoplasm from ubiquitin-mediated degradation remains elusive. In this study, a member of Angiomotin (Motin) family, AMOTL1 (Angiomotin Like 1), was screened out as the only one to promote YAP1 nuclear accumulation by several clinical cohorts, which was further confirmed by the cellular functional assays. The interaction between YAP1 and AMOTL1 was suggested by co-immunoprecipitation and immunofluorescent staining. The clinical significance of the AMOTL1–YAP1–CTGF axis in gastric cancer (GC) was analyzed by multiple clinical cohorts. Moreover, the therapeutic effect of targeting the oncogenic axis was appraised by drug-sensitivity tests and xenograft-formation assays. The upregulation of AMOTL1 is associated with unfavorable clinical outcomes of GC, and knocking down AMOTL1 impairs its oncogenic properties. The cytoplasmic interaction between AMOTL1 and YAP1 protects each other from ubiquitin-mediated degradation. AMOTL1 promotes YAP1 translocation into the nuclei to activate the downstream expression, such as CTGF. Knocking down AMOTL1, YAP1, and CTGF enhances the therapeutic efficacies of the first-line anticancer drugs. Taken together, AMOTL1 plays an oncogenic role in gastric carcinogenesis through interacting with YAP1 and promoting its nuclear accumulation. A combination of AMOTL1, YAP1, and CTGF expression might serve as a surrogate of Hippo activation status. The co-activation of the AMOTL1/YAP1–CTGF axis is associated with poor clinical outcomes of GC patients, and targeting this oncogenic axis may enhance the chemotherapeutic effects.

Published
2020

28. MMP-9 drives the melanomagenic transcription program through histone H3 tail proteolysis

Author

Nikhil Baban Ghate, Yonghwan Shin, Sungmin Kim, Suhn K. Rhie, and Woojin An

Subjects
Cancer Research, Gene knockdown, medicine.diagnostic_test, Melanoma, Proteolysis, Biology, medicine.disease, Cell biology, Chromatin, Histones, Histone H3, Mice, Matrix Metalloproteinase 9, RNA interference, Acetylation, Gene expression, Genetics, medicine, Animals, Humans, Molecular Biology
Abstract

Melanoma is a type of skin cancer that develops in pigment-producing melanocytes and often spreads to other parts of the body. Aberrant gene expression has been considered as a crucial step for increasing the risk of melanomagenesis, but how chromatin reorganization contributes to this pathogenic process is still not well understood. Here we report that matrix metalloproteinase 9 (MMP-9) localizes to the nucleus of melanoma cells and potentiates gene expression by proteolytically clipping the histone H3 N-terminal tail (H3NT). From genome-wide studies, we discovered that growth-regulatory genes are selectively targeted and activated by MMP-9-dependent H3NT proteolysis in melanoma cells. MMP-9 cooperates functionally with p300/CBP because MMP-9 cleaves H3NT in a manner that is dependent on p300/CBP-mediated acetylation of H3K18. The functional significance of MMP-9-dependent H3NT proteolysis is further underscored by the fact that RNAi knockdown and small-molecule inhibition of MMP-9 and p300/CBP impede melanomagenic gene expression and melanoma tumor growth. Together, our data establish new functions and mechanisms for nuclear MMP-9 in promoting melanomagenesis and demonstrate how MMP-9-dependent H3NT proteolysis can be exploited to prevent and treat melanoma skin cancer.

Published
2021

29. Quaking orchestrates a post-transcriptional regulatory network of endothelial cell cycle progression critical to angiogenesis and metastasis

Author

Lingegowda S. Mangala, James V. McCann, Gabriel Lopez-Berestein, Jinze Liu, Anil K. Sood, William Y. Kim, Chad V. Pecot, Trent A. Waugh, Andrew C. Dudley, Patrick L. Leslie, Harper L. Wilson, Emily B. Harrison, Alessandro Porrello, Adam R. Belanger, Xinan Liu, and Salma H. Azam

Subjects
0301 basic medicine, Cancer Research, Angiogenesis, Mice, Nude, Biology, Article, Metastasis, Neovascularization, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, RNA interference, Neoplasms, microRNA, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Animals, Humans, Gene silencing, Cyclin D1, Gene Regulatory Networks, Neoplasm Metastasis, Molecular Biology, Cells, Cultured, Cell Proliferation, Tumor microenvironment, Neovascularization, Pathologic, Cell Cycle, RNA-Binding Proteins, medicine.disease, Gene Expression Regulation, Neoplastic, HEK293 Cells, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer cell, Disease Progression, Cancer research, Female, RNA Interference, medicine.symptom
Abstract

Angiogenesis is critical to cancer development and metastasis. However, anti-angiogenic agents have only had modest therapeutic success, partly due to an incomplete understanding of tumor endothelial cell (EC) biology. We previously reported that the microRNA (miR)-200 family inhibits metastasis through regulation of tumor angiogenesis, but the underlying molecular mechanisms are poorly characterized. Here, using integrated bioinformatics approaches, we identified the RNA-binding protein (RBP) quaking (QKI) as a leading miR-200b endothelial target with previously unappreciated roles in the tumor microenvironment in lung cancer. In lung cancer samples, both miR-200b suppression and QKI overexpression corresponded with tumor ECs relative to normal ECs, and QKI silencing phenocopied miR-200b-mediated inhibition of sprouting. Additionally, both cancer cell and endothelial QKI expression in patient samples significantly corresponded with poor survival and correlated with angiogenic indices. QKI supported EC function by stabilizing cyclin D1 (CCND1) mRNA to promote EC G1/S cell cycle transition and proliferation. Both nanoparticle-mediated RNA interference of endothelial QKI expression and palbociclib blockade of CCND1 function potently inhibited metastasis in concert with significant effects on tumor vasculature. Altogether, this work demonstrates the clinical relevance and therapeutic potential of a novel, actionable miR/RBP axis in tumor angiogenesis and metastasis.

Published
2019

30. TRiC/CCT chaperonins are essential for organ growth by interacting with insulin/TOR signaling in Drosophila

Author

Kwang-Wook Choi and Ah-Ram Kim

Subjects
0301 basic medicine, Cancer Research, Chaperonins, genetic structures, Organogenesis, P70-S6 Kinase 1, Article, Animals, Genetically Modified, 03 medical and health sciences, 0302 clinical medicine, RNA interference, Genetics, Animals, Drosophila Proteins, Insulin, Wings, Animal, Molecular Biology, Protein kinase B, biology, Cell growth, TOR Serine-Threonine Kinases, Autophagy, Animal Structures, Gene Expression Regulation, Developmental, eye diseases, TOR signaling, Cell biology, 030104 developmental biology, Multiprotein Complexes, TOR signalling, 030220 oncology & carcinogenesis, biology.protein, Phosphorylation, Drosophila, Experimental organisms, sense organs, Chaperonin Containing TCP-1, Signal Transduction, RHEB
Abstract

Organ size is regulated by intercellular signaling for cell growth and proliferation. The TOR pathway mediates a key signaling mechanism for controlling cell size and number in organ growth. Chaperonin containing TCP-1 (CCT) is a complex that assists protein folding and function, but its role in animal development is largely unknown. Here we show that the CCT complex is required for organ growth by interacting with the TOR pathway in Drosophila. Reduction of CCT4 results in growth defects by affecting both cell size and proliferation. Loss of CCT4 causes preferential cell death anterior to the morphogenetic furrow in the eye disc and within wing pouch in the wing disc. Depletion of any CCT subunit in the eye disc results in headless phenotype. Overgrowth by active TOR signaling is suppressed by CCT RNAi. The CCT complex physically interacts with TOR signaling components including TOR, Rheb, and S6K. Loss of CCT leads to decreased phosphorylation of S6K and S6 while increasing phosphorylation of Akt. Insulin/TOR signaling is also necessary and sufficient for promoting CCT complex transcription. Our data provide evidence that the CCT complex regulates organ growth by directly interacting with the TOR signaling pathway.

Published
2019

31. Inhibition of TAZ contributes radiation-induced senescence and growth arrest in glioma cells

Author

Fangling Cheng, Dongsheng Guo, Baofeng Wang, Wei Li, Yiju Wei, Lei Zhang, and Lijun Zhang

Subjects
0301 basic medicine, Senescence, Cancer Research, Cell cycle checkpoint, DNA damage, Gene Expression, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, RNA interference, Glioma, Cell Line, Tumor, Radiation, Ionizing, Genetics, medicine, Humans, Molecular Biology, Cellular Senescence, beta Catenin, Cell Proliferation, Hippo signaling pathway, Axin Signaling Complex, Radiotherapy, Brain Neoplasms, Wnt signaling pathway, Intracellular Signaling Peptides and Proteins, Cell Cycle Checkpoints, medicine.disease, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Cancer research, Trans-Activators, Glioblastoma, Transcription Factors
Abstract

Glioblastoma (GBM) is the most aggressive brain tumor and resistant to current available therapeutics, such as radiation. To improve the clinical efficacy, it is important to understand the cellular mechanisms underlying tumor responses to radiation. Here, we investigated long-term cellular responses of human GBM cells to ionizing radiation. Comparing to the initial response within 12 hours, gene expression modulation at 7 days after radiation is markedly different. While genes related to cell cycle arrest and DNA damage responses are mostly modulated at the initial stage; immune-related genes are specifically affected as the long-term effect. This later response is associated with increased cellular senescence and inhibition of transcriptional coactivator with PDZ-binding motif (TAZ). Mechanistically, TAZ inhibition does not depend on the canonical Hippo pathway, but relies on enhanced degradation mediated by the β-catenin destruction complex in the Wnt pathway. We further showed that depletion of TAZ by RNAi promotes radiation-induced senescence and growth arrest. Pharmacological activation of the β-catenin destruction complex is able to promote radiation-induced TAZ inhibition and growth arrest in these tumor cells. The correlation between senescence and reduced expression of TAZ as well as β-catenin also occurs in human gliomas treated by radiation. Collectively, these findings suggested that inhibition of TAZ is involved in radiation-induced senescence and might benefit GBM radiotherapy.

Published
2018

32. Cell growth density modulates cancer cell vascular invasion via Hippo pathway activity and CXCR2 signaling.

Author

Sharif, G M, Schmidt, M O, Yi, C, Hu, Z, Haddad, B R, Glasgow, E, Riegel, A T, and Wellstein, A

Subjects
*CANCER cell growth, *CANCER invasiveness, *CHEMOKINE receptors, *HIPPOCAMPUS (Brain), *ENDOTHELIAL cells, *RNA interference, *CANCER treatment, *LABORATORY zebrafish
Abstract

Metastasis of cancer cells involves multiple steps, including their dissociation from the primary tumor and invasion through the endothelial cell barrier to enter the circulation and finding their way to distant organ sites where they extravasate and establish metastatic lesions. Deficient contact inhibition is a hallmark of invasive cancer cells, yet surprisingly the vascular invasiveness of commonly studied cancer cell lines is regulated by the density at which cells are propagated in culture. Cells grown at high density were less effective at invading an endothelial monolayer than cells grown at low density. This phenotypic difference was also observed in a zebrafish model of vascular invasion of cancer cells after injection into the yolk sac and extravasation of cancer cells into tissues from the vasculature. The vascular invasive phenotypes were reversible. A kinome-wide RNA interference screen was used to identify drivers of vascular invasion by panning small hairpin RNA (shRNA) library-transduced noninvasive cancer cell populations on endothelial monolayers. The selection of invasive subpopulations showed enrichment of shRNAs targeting the large tumor suppressor 1 (LATS1) kinase that inhibits the activity of the transcriptional coactivator yes-associated protein (YAP) in the Hippo pathway. Depletion of LATS1 from noninvasive cancer cells restored the invasive phenotype. Complementary to this, inhibition or depletion of YAP inhibited invasion in vitro and in vivo. The vascular invasive phenotype was associated with a YAP-dependent upregulation of the cytokines IL6, IL8 and C-X-C motif ligand 1, 2 and 3. Antibody blockade of cytokine receptors inhibited invasion and confirmed that they are rate-limiting drivers that promote cancer cell vascular invasiveness and could provide therapeutic targets. [ABSTRACT FROM AUTHOR]

Published
2015
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33. Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors.

Author

Labidi-Galy, S I, Clauss, A, Ng, V, Duraisamy, S, Elias, K M, Piao, H-Y, Bilal, E, Davidowitz, R A, Lu, Y, Badalian-Very, G, Györffy, B, Kang, U-B, Ficarro, S, Ganesan, S, Mills, G B, Marto, J A, and Drapkin, R

Subjects
*OVARIAN cancer, *BREAST cancer prognosis, *P53 protein, *GENETIC mutation, *MITOGEN-activated protein kinases, *RNA interference, *CANCER cell proliferation
Abstract

High-grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirm that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through the activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl-xL expression. We extended these findings into the examination of 1100 primary breast tumors and six breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with poor overall survival, suggesting that it may serve as a biomarker and therapeutic target in this setting. [ABSTRACT FROM AUTHOR]

Published
2015
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34. Systems level-based RNAi screening by high content analysis identifies UBR5 as a regulator of estrogen receptor-α protein levels and activity.

Author

Bolt, M J, Stossi, F, Callison, A M, Mancini, M G, Dandekar, R, and Mancini, M A

Subjects
*GENETICS of breast cancer, *RNA interference, *ESTROGEN receptors, *GENETIC testing, *TRANSCRIPTION factors, *GENE libraries, *DNA damage, *IMMUNE response
Abstract

Estrogen receptor-α (ERα) is a central transcription factor that regulates mammary gland physiology and a key driver in breast cancer. In the present study, we aimed to identify novel modulators of ERα-mediated transcriptional regulation via a custom-built siRNA library screen. This screen was directed against a variety of coregulators, transcription modifiers, signaling molecules and DNA damage response proteins. By utilizing a microscopy-based, multi-end point, estrogen responsive biosensor cell line platform, the primary screen identified a wide range of factors that altered ERα protein levels, chromatin remodeling and mRNA output. We then focused on UBR5, a ubiquitin ligase and known oncogene that modulates ERα protein levels and transcriptional output. Finally, we demonstrated that UBR5 also affects endogenous ERα target genes and E2-mediated cell proliferation in breast cancer cells. In conclusion, our multi-end point RNAi screen identified novel modulators of ERα levels and activity, and provided a robust systems level view of factors involved in mechanisms of nuclear receptor action and pathophysiology. Utilizing a high throughput RNAi screening approach we identified UBR5, a protein commonly amplified in breast cancer, as a novel regulator of ERα protein levels and transcriptional activity. [ABSTRACT FROM AUTHOR]

Published
2015
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35. Correction: AR-induced long non-coding RNA LINC01503 facilitates proliferation and metastasis via the SFPQ-FOSL1 axis in nasopharyngeal carcinoma

Author

Shi-Wei He, Cheng Xu, Ying-Qing Li, Ying-Qin Li, Yin Zhao, Pan-Pan Zhang, Yuan Lei, Ye-Lin Liang, Jun-Yan Li, Qian Li, Yang Chen, Sheng-Yan Huang, Jun Ma, and Na Liu

Subjects
Male, Cancer Research, Mice, Nude, Kaplan-Meier Estimate, Cell Line, Prognostic markers, Cell Line, Tumor, Genetics, Animals, Humans, Cell migration, Head and neck cancer, PTB-Associated Splicing Factor, Molecular Biology, Cell Proliferation, Mice, Inbred BALB C, Nasopharyngeal Carcinoma, Correction, Nasopharyngeal Neoplasms, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, HEK293 Cells, Receptors, Androgen, Lymphatic Metastasis, RNA Interference, RNA, Long Noncoding, Proto-Oncogene Proteins c-fos
Abstract

Increasing evidence indicates that long non-coding RNAs (lncRNAs) play vital roles in the tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in nasopharyngeal carcinoma (NPC) are still largely unknown. Our previous lncRNA expression profiles identified that LINC01503 was overexpressed in NPC. Here, we verified that LINC01503 was highly expressed in NPC and correlated with poor prognosis. LINC01503 promoted NPC cell proliferation, migration, and invasion in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, LINC01503 recruited splicing factor proline-and glutamine-rich (SFPQ) to activate Fos like 1 (FOSL1) transcription, and ectopic expression of FOSL1 reversed the suppressive effect of LINC01503 knockdown on NPC progression. Moreover, androgen receptor (AR)-mediated transcription activation was responsible for the overexpression of LINC01503, and AR ligand-dependent cell growth, migration, and invasion in NPC cells. Taken together, our findings reveal that AR-induced LINC01503 can promote NPC progression through the SFPQ-FOSL1 axis, which represents a novel prognostic biomarker and therapeutic target for NPC patients.

Published
2021

36. An in vivo RNAi screen identifies SALL1 as a tumor suppressor in human breast cancer with a role in CDH1 regulation.

Author

Wolf, J, Müller-Decker, K, Flechtenmacher, C, Zhang, F, Shahmoradgoli, M, Mills, G B, Hoheisel, J D, and Boettcher, M

Subjects
*RNA interference, *BREAST cancer, *CANCER cells, *ONCOGENIC viruses, *XENOTRANSPLANTATION, *TRANSCRIPTION factors
Abstract

The gold standard for determining the tumorigenic potential of human cancer cells is a xenotransplantation into immunodeficient mice. Higher tumorigenicity of cells is associated with earlier tumor onset. Here, we used xenotransplantation to assess the tumorigenic potential of human breast cancer cells following RNA interference-mediated inhibition of over 5000 genes. We identify 16 candidate tumor suppressors, one of which is the zinc-finger transcription factor SALL1. Analyzing this particular molecule in more detail, we show that inhibition of SALL1 correlates with reduced levels of CDH1, an important contributor to epithelial-to-mesenchymal transition. Furthermore, SALL1 expression led to an increased migration and more than twice as many cells expressing a cancer stem cell signature. Also, SALL1 expression correlates with the survival of breast cancer patients. These findings cast new light on a gene that has previously been described to be relevant during embryogenesis, but not carcinogenesis. [ABSTRACT FROM AUTHOR]

Published
2014
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37. Possible involvement of LKB1-AMPK signaling in non-homologous end joining.

Author

Ui, A, Ogiwara, H, Nakajima, S, Kanno, S, Watanabe, R, Harata, M, Okayama, H, Harris, C C, Yokota, J, Yasui, A, and Kohno, T

Subjects
*ADENOSINE monophosphate, *CELLULAR signal transduction, *TUMOR suppressor genes, *PEUTZ-Jeghers syndrome, *GENETIC disorders, *DNA repair, *RNA interference
Abstract

LKB1/STK11 is a tumor suppressor gene responsible for Peutz-Jeghers syndrome, an inherited cancer disorder associated with genome instability. The LKB1 protein functions in the regulation of cell proliferation, polarization and differentiation. Here, we suggest a role of LKB1 in non-homologous end joining (NHEJ), a major DNA double-strand break (DSB) repair pathway. LKB1 localized to DNA ends upon the generation of micro-irradiation and I-SceI endonuclease-induced DSBs. LKB1 inactivation either by RNA interference or by kinase-dead mutation compromised NHEJ-mediated DNA repair by suppressing the accumulation of BRM, a catalytic subunit of the SWI/SNF complex, at DSB sites, which promotes the recruitment of an essential NHEJ factor, KU70. AMPK2, a major substrate of LKB1 and a histone H2B kinase, was recruited to DSBs in an LKB1-dependent manner. AMPK2 depletion and a mutation of H2B that disrupted the AMPK2 phoshorylation site impaired KU70 and BRM recruitment to DSB sites. LKB1 depletion induced the formation of chromosome breaks and radials. These results suggest that LKB1-AMPK signaling controls NHEJ and contributes to genome stability. [ABSTRACT FROM AUTHOR]

Published
2014
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38. Engineering a single ubiquitin ligase for the selective degradation of all activated ErbB receptor tyrosine kinases.

Author

Kong, F, Zhang, J, Li, Y, Hao, X, Ren, X, Li, H, and Zhou, P

Subjects
*UBIQUITIN ligases, *EPIDERMAL growth factor receptors, *PROTEIN-tyrosine kinases, *BIODEGRADATION, *POST-translational modification, *RNA interference, *BREAST cancer treatment, *TARGETED drug delivery
Abstract

Interrogating specific cellular activities often entails the dissection of posttranslational modifications or functional redundancy conferred by protein families, which demands more sophisticated research tools than simply eliminating a specific gene product by gene targeting or RNA interference. We have developed a novel methodology that involves engineering a single SCFβTrCP-based ubiquitin ligase that is capable of not only simultaneously targeting the entire family of ErbB receptor tyrosine kinases for ubiquitination and degradation, but also selectively recruiting only activated ErbBs. The engineered SCFβTrCP ubiquitin ligase effectively blocked ErbB signaling and attenuated oncogenicity in breast cancer cells, yet had little effect on the survival and growth of non-cancerous breast epithelial cells. Therefore, engineering ubiquitin ligases offers a simple research tool to dissect the specific traits of tumorigenic protein families, and provides a rapid and feasible means to expand the dimensionality of drug discovery by assessing protein families or posttranslational modifications as potential drug targets. [ABSTRACT FROM AUTHOR]

Published
2014
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39. Identification of novel determinants of resistance to lapatinib in ERBB2-amplified cancers.

Author

Wetterskog, D, Shiu, K-K, Chong, I, Meijer, T, Mackay, A, Lambros, M, Cunningham, D, Reis-Filho, J S, Lord, C J, and Ashworth, A

Subjects
*BREAST cancer treatment, *LAPATINIB, *PROTO-oncogenes, *PROTEIN-tyrosine kinases, *GENETIC code, *PHENOTYPES, *HEALTH outcome assessment, *RNA interference, *THERAPEUTICS
Abstract

The gene encoding the receptor tyrosine kinase ERBB2, also known as HER2, is amplified and/or overexpressed in up to 15% of breast cancers. These tumours are characterised by an aggressive phenotype and poor clinical outcome. Although therapies targeted at ERBB2 have proven effective, many patients fail to respond to treatment or become resistant and the reasons for this are still largely unknown. Using a high-throughput functional screen we assessed whether genes found to be recurrently amplified and overexpressed in ERBB2+ve breast cancers mediate resistance to the ERBB2-targeted agent lapatinib. Lapatinib-resistant ERBB2-amplified breast cancer cell lines were screened, in the presence or absence of lapatinib, with an RNA interference library targeting 369 genes recurrently amplified and overexpressed in both ERBB2-amplified breast cancer tumours and cell lines. Small interfering RNAs targeting a number of genes caused sensitivity to lapatinib in this context. The mechanisms of resistance conferred by the identified genes were further investigated and in the case of NIBP (TRAPPC9), lapatinib resistance was found to be mediated through NF-κB signalling. Our results indicate that specific amplified and/ or overexpressed genes found in ERBB2-amplified breast cancer may mediate response to ERBB2-targeting agents. [ABSTRACT FROM AUTHOR]

Published
2014
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40. RNAi-mediated stathmin suppression reduces lung metastasis in an orthotopic neuroblastoma mouse model.

Author

Byrne, F L, Yang, L, Phillips, P A, Hansford, L M, Fletcher, J I, Ormandy, C J, McCarroll, J A, and Kavallaris, M

Subjects
*RNA interference, *STATHMIN, *TUMOR suppressor genes, *NEUROBLASTOMA, *LUNG cancer treatment, *CHILDHOOD cancer, *LABORATORY mice, *TUMOR proteins
Abstract

Metastatic neuroblastoma is an aggressive childhood cancer of neural crest origin. Stathmin, a microtubule destabilizing protein, is highly expressed in neuroblastoma although its functional role in this malignancy has not been addressed. Herein, we investigate stathmin's contribution to neuroblastoma tumor growth and metastasis. Small interfering RNA (siRNA)-mediated stathmin suppression in two independent neuroblastoma cell lines, BE(2)-C and SH-SY5Y, did not markedly influence cell proliferation, viability or anchorage-independent growth. In contrast, stathmin suppression significantly reduced cell migration and invasion in both the neuroblastoma cell lines. Stathmin suppression altered neuroblastoma cell morphology and this was associated with changes in the cytoskeleton, including increased tubulin polymer levels. Stathmin suppression also modulated phosphorylation of the actin-regulatory proteins, cofilin and myosin light chain (MLC). Treatment of stathmin-suppressed neuroblastoma cells with the ROCKI and ROCKII inhibitor, Y-27632, ablated MLC phosphorylation and returned the level of cofilin phosphorylation and cell invasion back to that of untreated control cells. ROCKII inhibition (H-1152) and siRNA suppression also reduced cofilin phosphorylation in stathmin-suppressed cells, indicating that ROCKII mediates stathmin's regulation of cofilin phosphorylation. This data demonstrates a link between stathmin and the regulation of cofilin and MLC phosphorylation via ROCK. To examine stathmin's role in neuroblastoma metastasis, stathmin short hairpin RNA (shRNA)\luciferase-expressing neuroblastoma cells were injected orthotopically into severe combined immunodeficiency-Beige mice, and tumor growth monitored by bioluminescent imaging. Stathmin suppression did not influence neuroblastoma cell engraftment or tumor growth. In contrast, stathmin suppression significantly reduced neuroblastoma lung metastases by 71% (P<0.008) compared with control. This is the first study to confirm a role for stathmin in hematogenous spread using a clinically relevant orthotopic cancer model, and has identified stathmin as an important contributor of cell invasion and metastasis in neuroblastoma. [ABSTRACT FROM AUTHOR]

Published
2014
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41. Selective regulation of p38β protein and signaling by integrin-linked kinase mediates bladder cancer cell migration.

Author

Yu, L, Yuan, X, Wang, D, Barakat, B, Williams, E D, and Hannigan, G E

Subjects
*BLADDER cancer, *CANCER cell migration, *INTEGRIN-linked kinase, *PROTEIN kinases, *CYTOSKELETON, *RNA interference, *CELLULAR signal transduction
Abstract

Integrin-linked kinase (ILK) and p38MAPK are protein kinases that transduce extracellular signals regulating cell migration and actin cytoskeletal organization. ILK-dependent regulation of p38MAPK is critical for mammalian kidney development and in smooth muscle cell migration, however, specific p38 isoforms has not been previously examined in ILK-regulated responses. Signaling by ILK and p38MAPK is often dysregulated in bladder cancer, and here we report a strong positive correlation between protein levels of ILK and p38β, which is the predominant isoform found in bladder cancer cells, as well as in patient-matched normal bladder and tumor samples. Knockdown by RNA interference of either p38β or ILK disrupts serum-induced, Rac1-dependent migration and actin cytoskeletal organization in bladder cancer cells. Surprisingly, ILK knockdown causes the selective reduction in p38β cellular protein level, without inhibiting p38β messenger RNA (mRNA) expression. The loss of p38β protein in ILK-depleted cells is partially rescued by the 26S proteasomal inhibitor MG132. Using co-precipitation and bimolecular fluorescent complementation assays, we find that ILK selectively forms cytoplasmic complexes with p38β. In situ proximity ligation assays further demonstrate that serum-stimulated assembly of endogenous ILK-p38β complexes is sensitive to QLT-0267, a small molecule ILK kinase inhibitor. Finally, inhibition of ILK reduces the amplitude and period of serum-induced activation of heat shock protein 27 (Hsp27), a target of p38β implicated in actin cytoskeletal reorganization. Our work identifies Hsp27 as a novel target of ILK-p38β signaling complexes, playing a key role in bladder cancer cell migration. [ABSTRACT FROM AUTHOR]

Published
2014
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42. PARP14 regulates cyclin D1 expression to promote cell-cycle progression

Author

George Lucian Moldovan, Tanay Thakar, Michael J. O’Connor, and Claudia M. Nicolae

Subjects
0301 basic medicine, Cancer Research, Poly ADP ribose polymerase, RNA Stability, Regulator, Biology, Retinoblastoma Protein, Article, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Cyclin D1, Genetics, medicine, Humans, Luciferase, RNA, Messenger, RNA, Small Interfering, Molecular Biology, 3' Untranslated Regions, Polymerase, Messenger RNA, Retinoblastoma, Cell Cycle, medicine.disease, G1 Phase Cell Cycle Checkpoints, Cell biology, 030104 developmental biology, Gene Expression Regulation, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, biology.protein, RNA Interference, Signal transduction, Poly(ADP-ribose) Polymerases, E2F1 Transcription Factor
Abstract

Cyclin D1 is an essential regulator of the G1–S cell-cycle transition and is overexpressed in many cancers. Expression of cyclin D1 is under tight cellular regulation that is controlled by many signaling pathways. Here we report that PARP14, a member of the poly(ADP-ribose) polymerase (PARP) family, is a regulator of cyclin D1 expression. Depletion of PARP14 leads to decreased cyclin D1 protein levels. In cells with a functional retinoblastoma (RB) protein pathway, this results in G1 cell-cycle arrest and reduced proliferation. Mechanistically, we found that PARP14 controls cyclin D1 mRNA levels. Using luciferase assays, we show that PARP14 specifically regulates cyclin D1 3′UTR mRNA stability. Finally, we also provide evidence that G1 arrest in PARP14-depleted cells is dependent on an intact p53–p21 pathway. Our work uncovers a new role for PARP14 in promoting cell-cycle progression through both cyclin D1 and the p53 pathway.

Published
2020

43. NORE1A directs apoptotic switch of TNF signaling through reciprocal modulation of ITCH-mediated destruction of TNFRI and BAX

Author

Seong In Jeong, Min Goo Lee, Ji Sun Lim, Kyung Phil Ko, Kyung Woo Lee, and Sung Gil Chi

Subjects
0301 basic medicine, Cancer Research, Ubiquitin-Protein Ligases, Apoptosis, medicine.disease_cause, law.invention, 03 medical and health sciences, Mice, 0302 clinical medicine, Ubiquitin, Transcription (biology), law, Cell Line, Tumor, Genetics, medicine, Cytotoxic T cell, Animals, Humans, Fibroblast, Molecular Biology, Adaptor Proteins, Signal Transducing, bcl-2-Associated X Protein, biology, Tumor Necrosis Factor-alpha, NF-kappa B, HCT116 Cells, Survival Analysis, Xenograft Model Antitumor Assays, Cell biology, Gene Expression Regulation, Neoplastic, Repressor Proteins, 030104 developmental biology, medicine.anatomical_structure, Receptors, Tumor Necrosis Factor, Type I, 030220 oncology & carcinogenesis, biology.protein, Suppressor, Tumor necrosis factor alpha, RNA Interference, Carcinogenesis, Apoptosis Regulatory Proteins, HeLa Cells, Signal Transduction
Abstract

NORE1A (RASSF5) is a tumor suppressor of the Ras-association domain family (RASSF) that is commonly inactivated in multiple human cancers. However, the molecular mechanism underlying its growth inhibition function remains largely undefined. Here we report that NORE1A antagonizes tumor necrosis factor receptor I (TNFRI) through the assembly of ITCH-mediated destruction complex to suppress TNF-NF-κB signaling and tumorigenesis. Moreover, NORE1A is identified as a transcription target of NF-κB, which directs an apoptotic switch of TNF effect by blocking ITCH interaction with and ubiquitination of BAX. Mechanistically, NORE1A binds directly to TNFRI and ITCH via the C1 and PPXY domains, respectively to facilitate the formation of ITCH-mediated destruction complex followed by ubiquitination-mediated lysosomal degradation of TNFRI. Through this function, NORE1A suppresses TNF-induced NF-κB-mediated transcription of pro-inflammatory and tumor-promoting genes, epithelial-to-mesenchymal transition, invasion and migration of tumor cells, and also debilitates tumor cell activation of macrophage and fibroblast. While NORE1A suppresses TNF receptor-mediated apoptosis, it activates TNF-induced apoptosis through BAX activation by protecting BAX from ITCH binding and ubiquitination. Cytotoxic response to TNF is substantially attenuated in NORE1A-depleted cells and tumors, and NORE1A-induced tumor regression is highly impeded in BAX-depleted tumors. An inverse correlation is shown between NORE1A and TNFRI expression in both cancer cell lines and primary tumors, and NORE1A effect on survival of cancer patients is strongly associated with expression status of ITCH. Collectively, this study uncovers that NORE1A directs a substrate switch of ITCH favoring TNFRI over BAX to terminate TNF signaling and accelerate apoptosis, illuminating the mechanistic consequence of NORE1A inactivation in tumorigenesis.

Published
2020

44. AR and ERG drive the expression of prostate cancer specific long noncoding RNAs

Author

Alfonso Urbanucci, Mina Sattari, Tapio Visakorpi, Matti Annala, Leena Latonen, Juha Kesseli, Kati Kivinummi, Annika Kohvakka, Matti Nykter, Anastasia Shcherban, Teuvo L.J. Tammela, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University

Subjects
0301 basic medicine, Biochemical recurrence, Hepatocyte Nuclear Factor 3-alpha, Male, Cancer Research, Biolääketieteet - Biomedicine, Biology, Genome, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Transcriptional Regulator ERG, Transcription (biology), Cell Movement, Syöpätaudit - Cancers, Cell Line, Tumor, Genetics, medicine, Humans, Prospective Studies, Molecular Biology, Gene, Transcription factor, Cell Proliferation, Homeodomain Proteins, Prostatic Neoplasms, medicine.disease, In vitro, 3. Good health, Androgen receptor, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Receptors, Androgen, 030220 oncology & carcinogenesis, Cancer research, Disease Progression, RNA Interference, RNA, Long Noncoding
Abstract

Long noncoding RNAs (lncRNAs) play pivotal roles in cancer development and progression, and some function in a highly cancer-specific manner. However, whether the cause of their expression is an outcome of a specific regulatory mechanism or nonspecific transcription induced by genome reorganization in cancer remains largely unknown. Here, we investigated a group of lncRNAs that we previously identified to be aberrantly expressed in prostate cancer (PC), called TPCATs. Our high-throughput real-time PCR experiments were integrated with publicly available RNA-seq and ChIP-seq data and revealed that the expression of a subset of TPCATs is driven by PC-specific transcription factors (TFs), especially androgen receptor (AR) and ETS-related gene (ERG). Our in vitro validations confirmed that AR and ERG regulated a subset of TPCATs, most notably for EPCART. Knockout of EPCART was found to reduce migration and proliferation of the PC cells in vitro. The high expression of EPCART and two other TPCATs (TPCAT-3-174133 and TPCAT-18-31849) were also associated with the biochemical recurrence of PC in prostatectomy patients and were independent prognostic markers. Our findings suggest that the expression of numerous PC-associated lncRNAs is driven by PC-specific mechanisms and not by random cellular events that occur during cancer development. Furthermore, we report three prospective prognostic markers for the early detection of advanced PC and show EPCART to be a functionally relevant lncRNA in PC.

Published
2020

45. WSTF acetylation by MOF promotes WSTF activities and oncogenic functions

Author

Min Li, Yan-Kun Liu, Ya-Qi Wang, Xiao-Jun Zhang, Cheng-Hua Yu, Shu-Qing Wang, Yufeng Li, Yuhui Li, De-Yan Li, Yan Liu, Yuan-Yue Zhang, Jiang-Sheng Mi, Yue-Hong Long, and Jing-Hua Zhang

Subjects
0301 basic medicine, Cancer Research, Carcinogenesis, Transplantation, Heterologous, Mice, Nude, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Sirtuin 1, Cell Movement, Cell Line, Tumor, Neoplasms, Genetics, Animals, Humans, Neoplasm Invasiveness, Phosphorylation, RNA, Small Interfering, Molecular Biology, Transcription factor, Cell Proliferation, Histone Acetyltransferases, Regulation of gene expression, Mice, Inbred BALB C, Kinase, HEK 293 cells, Acetylation, Cell biology, Transplantation, 030104 developmental biology, HEK293 Cells, Gene Expression Regulation, 030220 oncology & carcinogenesis, Female, RNA Interference, Tyrosine kinase, Protein Processing, Post-Translational, Neoplasm Transplantation, Transcription Factors
Abstract

Williams syndrome transcription factor (WSTF) is a transcription factor and tyrosine kinase. WSTF overexpression promotes migration and proliferation of various cancers, and Ser158 (WSTFS158) phosphorylation plays an important role in this process. However, the role of the other posttranslational modifications of WSTF is unknown. Here, we report that lysine (K) 426 on WSTF is acetylated by MOF and deacetylated by SIRT1. Mechanistically, male-specific lethal (MSL) 1v1 interaction with WSTF facilitates its interaction with MOF for WSTF acetylation, which in turn promotes WSTFS158 phosphorylation. The kinase and transcriptional regulatory activity of WSTF were enhanced by acetylation. WSTFK426ac levels positively and significantly correlated with tumor size, histological grade, and age. Moreover, we demonstrated that acetylated WSTF promotes cancer cell proliferation, migration, invasion, and tumor formation. In conclusion, we identified the enzymes regulating WSTF K426 acetylation, and demonstrated an acetylation-dependent mechanism that modulates the activities of WSTF and contributes to tumorigenesis. Our findings provide new clues to study WSTF-mediated normal development and disease.

Published
2020

46. Deoxycholic acid modulates the progression of gallbladder cancer through N

Author

Ruirong, Lin, Ming, Zhan, Linhua, Yang, Hui, Wang, Hui, Shen, Shuai, Huang, Xince, Huang, Sunwang, Xu, Zijie, Zhang, Weijian, Li, Qiang, Liu, Yongsheng, Shi, Wei, Chen, Jianxiu, Yu, and Jian, Wang

Subjects
Male, Mice, Inbred BALB C, Adenosine, Mice, Nude, Xenograft Model Antitumor Assays, Article, Non-coding RNAs, Gene Expression Regulation, Neoplastic, MicroRNAs, HEK293 Cells, Cell Line, Tumor, Disease Progression, Animals, Humans, Biliary tract cancer, Gallbladder Neoplasms, RNA Interference, Cell Proliferation, Deoxycholic Acid, Cell signalling
Abstract

Bile acids (BAs), well-defined signaling molecules with diverse metabolic functions, play important roles in cellular processes associated with many cancers. As one of the most common BAs, deoxycholic acid (DCA) is originally synthesized in the liver, stored in the gallbladder, and processed in the gut. DCA plays crucial roles in various tumors; however, functions and molecular mechanisms of DCA in gallbladder cancer (GBC) still remain poorly characterized. Here, we analyzed human GBC samples and found that DCA was significantly downregulated in GBC, and reduced levels of DCA was associated with poor clinical outcome in patients with GBC. DCA treatment impeded tumor progression by halting cell proliferation. DCA decreased miR-92b-3p expression in an m6A-dependent posttranscriptional modification manner by facilitating dissociation of METTL3 from METTL3–METTL14–WTAP complex, which increased the protein level of the phosphatase and tensin homolog, a newly identified target of miR-92b-3p, and subsequently inactivated the PI3K/AKT signaling pathway. Our findings revealed that DCA might function as a tumor suppressive factor in GBC at least by interfering with miR-92b-3p maturation, and suggested that DCA treatment could provide a new therapeutic strategy for GBC.

Published
2020

47. The FOXC1/FBP1 signaling axis promotes colorectal cancer proliferation by enhancing the Warburg effect

Author

Ye Xu, Dawei Li, Keping Xie, Yaqi Li, Jitao Wu, Ping Wei, Guichao Li, Qingguo Li, Xinxiang Li, Meng Zhang, Sanjun Cai, and Dacheng Xie

Subjects
0301 basic medicine, Cancer Research, Transcription, Genetic, Colorectal cancer, Recombinant Fusion Proteins, Cell, Mice, Nude, Apoptosis, Kaplan-Meier Estimate, Adenocarcinoma, Biology, medicine.disease_cause, Disease-Free Survival, Cohort Studies, Mice, 03 medical and health sciences, 0302 clinical medicine, RNA interference, Databases, Genetic, Tumor Cells, Cultured, Genetics, medicine, Animals, Humans, Gene silencing, RNA, Messenger, RNA, Neoplasm, RNA, Small Interfering, Promoter Regions, Genetic, Molecular Biology, Tissue microarray, Cell Cycle, Forkhead Transcription Factors, Cell cycle, medicine.disease, Warburg effect, eye diseases, Fructose-Bisphosphatase, Neoplasm Proteins, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Heterografts, RNA Interference, sense organs, Colorectal Neoplasms, Carcinogenesis, Signal Transduction
Abstract

Aberrant expression of Forkhead box (FOX) transcription factors plays vital roles in carcinogenesis. However, the function of the FOX family member FOXC1 in maintenance of colorectal cancer (CRC) malignancy is unknown. Herein, FOXC1 expression in CRC specimens in The Cancer Genome Atlas (TCGA) cohort was analyzed and validated using immunohistochemistry with a tissue microarray. The effect of FOXC1 expression on proliferation of and glycolysis in CRC cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. Our results showed that FOXC1 expression was higher in CRC specimens than in adjacent benign tissue specimens. Univariate survival analyses of the patients from whom the study specimens were obtained, and validated cohorts indicated that ectopic FOXC1 expression was significantly correlated with shortened survival. Silencing FOXC1 expression in CRC cells inhibited their proliferation and colony formation and decreased their glucose consumption and lactate production. In contrast, FOXC1 overexpression had the opposite effect. Furthermore, increased expression of FOXC1 downregulated that of a key glycolytic enzyme, fructose-1,6-bisphosphatase 1 (FBP1). Mechanistically, FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Collectively, aberrant FBP1 expression contributed to CRC tumorigenicity, and decreased FBP1 expression coupled with increased FOXC1 expression provided better prognostic information than did FOXC1 expression alone. Therefore, the FOXC1/FBP1 axis induces CRC cell proliferation, reprograms metabolism in CRCs, and constitutes potential prognostic predictors and therapeutic targets for CRC.

Published
2018

48. Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI

Author

Chi Liu, Ruo-Yu Tseng, Jim-Min Fang, Yu-Chin Lin, Jin-Yuan Shih, Chien-Hui Weng, Ching-Chow Chen, Yi-Ting Lin, An-Chieh Chiu, Li-Yu Chen, Yun-Chieh Lin, and Yu-Hsuan Yeh

Subjects
0301 basic medicine, Cancer Research, Lung Neoplasms, Vimentin, Piperazines, Tyrosine-kinase inhibitor, Mice, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Osimertinib, Epidermal growth factor receptor, RNA, Small Interfering, Mice, Inbred BALB C, Gene knockdown, Aniline Compounds, biology, Gefitinib, Cadherins, Neoplasm Proteins, Specific Pathogen-Free Organisms, ErbB Receptors, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, RNA Interference, Proto-oncogene tyrosine-protein kinase Src, medicine.drug, Epithelial-Mesenchymal Transition, medicine.drug_class, Ubiquitin-Protein Ligases, Mice, Nude, Antineoplastic Agents, 03 medical and health sciences, Antigens, CD, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Epithelial–mesenchymal transition, Protein Kinase Inhibitors, neoplasms, Molecular Biology, Acrylamides, Zinc Finger E-box-Binding Homeobox 1, respiratory tract diseases, Histone Deacetylase Inhibitors, 030104 developmental biology, Drug Resistance, Neoplasm, biology.protein, Cancer research, Drug Screening Assays, Antitumor, Hydroxymethylglutaryl-CoA Reductase Inhibitors
Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is a major advance in treating NSCLC with EGFR-activating mutations. However, acquired resistance, due partially to secondary mutations limits their use. Here we report that NSCLC cells with acquired resistance to gefitinib or osimertinib (AZD9291) exhibit EMT features, with a decrease in E-cadherin, and increases in vimentin and stemness, without possessing any EGFR secondary mutations. Knockdown of E-cadherin in parental cells increased gefitinib resistance and stemness, while knockdown of vimentin in resistant cells resulted in opposite effects. Src activation and Hakai upregulation were found in gefitinib-resistant cells. Knockdown of Hakai elevated E-cadherin expression, attenuated stemness, and resensitized the cells to gefitinib. Clinical cancer specimens with acquired gefitinib resistance also showed a decrease in E-cadherin and an increase in Hakai expression. The dual HDAC and HMGR inhibitor JMF3086 inhibited the Src/Hakai and Hakai/E-cadherin interaction to reverse E-cadherin expression, and attenuated vimentin and stemness to restore gefitinib sensitivity. The EMT features of AZD9291-resistant H1975 cells were related to the upregulation of Zeb1. Both gefitinib and AZD9291 sensitivity was restored by JMF3086 through reversing EMT. Our study not only revealed a common mechanism of EMT in both gefitinib and AZD9291 resistance beyond EGFR mutations per se, but also provides a new strategy to overcome it.

Published
2018

49. Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade

Author

Shauna N. Vasilatos, Zhishen Cao, Ye Qin, Yi Huang, Nancy E. Davidson, Binfeng Lu, Steffi Oesterreich, Min Huang, Anda M. Vlad, Yumei Fu, Lin Chen, and Hao Wu

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Triple Negative Breast Neoplasms, CD8-Positive T-Lymphocytes, B7-H1 Antigen, Mice, Chemokine receptor, Antineoplastic Agents, Immunological, 0302 clinical medicine, Tumor Microenvironment, RNA, Small Interfering, Promoter Regions, Genetic, Histone Demethylases, Mice, Inbred BALB C, Neoplasm Proteins, Histone Code, medicine.anatomical_structure, 030220 oncology & carcinogenesis, CXCL9, Female, RNA Interference, Immunotherapy, Chemokines, LSD1/KDM1A, LSD1 inhibitor, T cell, Mice, Nude, Antineoplastic Agents, Biology, PD-1/PD-L1, Methylation, Article, CCL5, T-cell chemokine, 03 medical and health sciences, breast cancer, Cell Line, Tumor, Genetics, medicine, Animals, Humans, CXCL10, Molecular Biology, Tumor microenvironment, Xenograft Model Antitumor Assays, Immune checkpoint, Histone Deacetylase Inhibitors, 030104 developmental biology, Cancer research, Tumor Escape
Abstract

Immunotherapy strategies have been emerging as powerful weapons against cancer. Early clinical trials reveal that overall response to immunotherapy is low in breast cancer patients, suggesting that effective strategies to overcome resistance to immunotherapy are urgently needed. In this study, we investigated whether epigenetic reprograming by modulating histone methylation could enhance effector T lymphocyte trafficking and improve therapeutic efficacy of immune checkpoint blockade in breast cancer with focus on triple-negative breast cancer (TNBC) subtype. In silico analysis of The Cancer Genome Atlas (TCGA) data shows that expression of histone lysine-specific demethylase 1 (LSD1) is inversely associated with the levels of cytotoxic T cell-attracting chemokines (C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 9 and 10 (CXCL9, CXCL10)) and programmed death-ligand 1 (PD-L1) in clinical TNBC specimens. Tiling chromatin immunoprecipitation study showed that re-expression of chemokines by LSD1 inhibition is associated with increased H3K4me2 levels at proximal promoter regions. Rescue experiments using concurrent treatment with small interfering RNA or inhibitor of chemokine receptors blocked LSD1 inhibitor-enhanced CD8+ T cell migration, indicating a critical role of key T cell chemokines in LSD1-mediated CD8+ lymphocyte trafficking to the tumor microenvironment. In mice bearing TNBC xenograft tumors, anti-PD-1 antibody alone failed to elicit obvious therapeutic effect. However, combining LSD1 inhibitors with PD-1 antibody significantly suppressed tumor growth and pulmonary metastasis, which was associated with reduced Ki-67 level and augmented CD8+ T cell infiltration in xenograft tumors. Overall, these results suggest that LSD1 inhibition may be an effective adjuvant treatment with immunotherapy as a novel management strategy for poorly immunogenic breast tumors.

Published
2018

50. Polo-like kinases and acute leukemia

Author

Linda Vidarsdottir, Iryna Kolosenko, Caroline Palm-Apergi, Oksana Goroshchuk, and Alireza Azimi

Subjects
Adult, 0301 basic medicine, PLK4, Cancer Research, Antineoplastic Agents, Cell Cycle Proteins, Polo-like kinase, Protein Serine-Threonine Kinases, Biology, PLK1, Gene Expression Regulation, Enzymologic, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, RNA interference, Proto-Oncogene Proteins, Antineoplastic Combined Chemotherapy Protocols, Genetics, Animals, Humans, Molecular Targeted Therapy, Child, Protein Kinase Inhibitors, Molecular Biology, Clinical Trials as Topic, Acute leukemia, Leukemia, Gene Expression Regulation, Leukemic, Kinase, Tumor Suppressor Proteins, Hematopoietic Stem Cell Transplantation, Volasertib, Combined Modality Therapy, Neoplasm Proteins, Survival Rate, Clinical trial, 030104 developmental biology, chemistry, Multigene Family, 030220 oncology & carcinogenesis, Acute Disease, Cancer research, RNA Interference, Drug Screening Assays, Antitumor
Abstract

Acute leukemia is a common malignancy among children and adults worldwide and many patients suffer from chronic health issues using current therapeutic approaches. Therefore, there is a great need for the development of novel and more specific therapies with fewer side effects. The family of Polo-like kinases (Plks) is a group of five serine/threonine kinases that play an important role in cell cycle regulation and are critical targets for therapeutic invention. Plk1 and Plk4 are novel targets for cancer therapy as leukemic cells often express higher levels than normal cells. In contrast, Plk2 and Plk3 are considered to be tumor suppressors. Several small molecule inhibitors have been developed for targeting Plk1 inhibition. Despite reaching phase III clinical trials, one of the ATP-competitive Plk1 inhibitor, volasertib, did not induce an objective clinical response and even caused lethal side effects in some patients. In order to improve the specificity of the Plk1 inhibitors and reduce off-target side effects, novel RNA interference (RNAi)-based therapies have been developed. In this review, we summarize the mechanisms of action of the Plk family members in acute leukemia, describe preclinical studies and clinical trials involving Plk-targeting drugs and discuss novel approaches in Plk targeting.

Published
2018

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