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The roles of RNA modification during organ metastasis of cancer cells are not known. Here we established breast cancer lung metastasis cells by three rounds of selection of lung metastatic subpopulations in vivo and designated them as BCLMF3 cells. In these cells, mRNA N6-methyladenosine (m6A) and methyltransferase METTL3 were increased, while the demethylase FTO was decreased. Epi-transcriptome and transcriptome analyses together with functional studies identified keratin 7 (KRT7) as a key effector for m6A-induced breast cancer lung metastasis. Specifically, increased METTL3 methylated KRT7-AS at A877 to increase the stability of a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes. Furthermore, YTHDF1/eEF-1 was involved in FTO-regulated translational elongation of KRT7 mRNA, with methylated A950 in KRT7 exon 6 as the key site for methylation. In vivo and clinical studies confirmed the essential roles of KRT7, KRT7-AS, and METTL3 for lung metastasis and clinical progression of breast cancer. Collectively, m6A promotes breast cancer lung metastasis by increasing the stability of a KRT7-AS/KRT7 mRNA duplex and translation of KRT7.Significance:This study suggests that N6-methyladenosine is a key driver and potential therapeutic target in breast cancer metastasis.

Studies on biological functions of RNA modifications such as

Studies on biological functions of RNA modifications such as N 6 -methyladenosine (m 6 A) in mRNA have sprung up in recent years, while the roles of N 1 -methyladenosine (m 1 A) in cancer progression remain largely unknown. We find m 1 A demethylase ALKBH3 can regulate the glycolysis of cancer cells via a demethylation activity dependent manner. Specifically, sequencing and functional studies confirm that ATP5D, one of the most important subunit of adenosine 5′-triphosphate synthase, is involved in m 1 A demethylase ALKBH3-regulated glycolysis of cancer cells. The m 1 A modified A71 at the exon 1 of ATP5D negatively regulates its translation elongation via increasing the binding with YTHDF1/eRF1 complex, which facilitates the release of message RNA (mRNA) from ribosome complex. m 1 A also regulates mRNA stability of E2F1, which directly binds with ATP5D promoter to initiate its transcription. Targeted specific demethylation of ATP5D m 1 A by dm 1 ACRISPR system can significantly increase the expression of ATP5D and glycolysis of cancer cells. In vivo data confirm the roles of m 1 A/ATP5D in tumor growth and cancer progression. Our study reveals a crosstalk of mRNA m 1 A modification and cell metabolism, which expands the understanding of such interplays that are essential for cancer therapeutic application.

The roles of RNA modification during organ metastasis of cancer cells are not known. Here we established breast cancer lung metastasis cells by three rounds of selection of lung metastatic subpopulations in vivo and designated them as BCLMF3 cells. In these cells, mRNA N6-methyladenosine (m6A) and methyltransferase METTL3 were increased, while the demethylase FTO was decreased. Epi-transcriptome and transcriptome analyses together with functional studies identified keratin 7 (KRT7) as a key effector for m6A-induced breast cancer lung metastasis. Specifically, increased METTL3 methylated KRT7-AS at A877 to increase the stability of a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes. Furthermore, YTHDF1/eEF-1 was involved in FTO-regulated translational elongation of KRT7 mRNA, with methylated A950 in KRT7 exon 6 as the key site for methylation. In vivo and clinical studies confirmed the essential roles of KRT7, KRT7-AS, and METTL3 for lung metastasis and clinical progression of breast cancer. Collectively, m6A promotes breast cancer lung metastasis by increasing the stability of a KRT7-AS/KRT7 mRNA duplex and translation of KRT7. Significance: This study suggests that N6-methyladenosine is a key driver and potential therapeutic target in breast cancer metastasis.

Background tRNA-derived small RNAs (tDRs), which are widely distributed in human tissues including blood and urine, play an important role in the progression of cancer. However, the expression of tDRs in colorectal cancer (CRC) plasma and their potential diagnostic values have not been systematically explored. Methods The expression profiles of tDRs in plasma of CRC and health controls (HCs) are investigated by small RNA sequencing. The level and diagnostic value of 5′-tRF-GlyGCC are evaluated by quantitative PCR in plasma samples from 105 CRC patients and 90 HCs. The mechanisms responsible for biogenesis of 5′-tRF-GlyGCC are checked by in vitro and in vivo models. Results 5′-tRF-GlyGCC is dramatically increased in plasma of CRC patients compared to that of HCs. The area under curve (AUC) for 5′-tRF-GlyGCC in CRC group is 0.882. The combination of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) with 5′-tRF-GlyGCC improves the AUC to 0.926. Consistently, the expression levels of 5′-tRF-GlyGCC in CRC cells and xenograft tissues are significantly greater than that in their corresponding controls. Blood cells co-cultured with CRC cells or mice xenografted with CRC tumors show increased levels of 5′-tRF-GlyGCC. In addition, we find that the increased expression of 5′-tRF-GlyGCC is dependent on the upregulation of AlkB homolog 3 (ALKBH3), a tRNA demethylase which can promote tRNA cleaving to generate tDRs. Conclusions The level of 5′-tRF-GlyGCC in plasma is a promising diagnostic biomarker for CRC diagnosis.

The mechanistic action of bromodomain-containing protein 4 (BRD4) in cancer motility, including epithelial-mesenchymal transition (EMT), remains largely undefined. We found that targeted inhibition of BRD4 reduces migration, invasion, in vivo growth of patient-derived xenograft (PDX), and lung colonization of breast cancer (BC) cells. Inhibition of BRD4 rapidly decreases the expression of Snail, a powerful EMT transcription factor (EMT-TF), via diminishing its protein stability and transcription. Protein kinase D1 (PRKD1) is responsible for BRD4-regulated Snail protein stability by triggering phosphorylation at Ser11 of Snail and then inducing proteasome-mediated degradation. BRD4 inhibition also suppresses the expression of Gli1, a key transductor of Hedgehog (Hh) required to activate the transcription of SNAI1, in BC cells. The GACCACC sequence (−341 to −333) in the SNAI1 promoter is responsible for Gli1-induced transcription of SNAI1. Clinically, BRD4 and Snail levels are increased in lung-metastasized, estrogen receptor-negative (ER-), and progesterone receptor-negative (PR-) breast cancers and correlate with the expression of mesenchymal markers. Collectively, BRD4 can regulate malignancy of breast cancer cells via both transcriptional and post-translational regulation of Snail.

Transfer RNA is heavily modified and plays a central role in protein synthesis and cellular functions. Here we demonstrate that ALKBH3 is a 1-methyladenosine (m1A) and 3-methylcytidine (m3C) demethylase of tRNA. ALKBH3 can promote cancer cell proliferation, migration and invasion. In vivo study confirms the regulation effects of ALKBH3 on growth of tumor xenograft. The m1A demethylated tRNA is more sensitive to angiogenin (ANG) cleavage, followed by generating tRNA-derived small RNAs (tDRs) around the anticodon regions. tDRs are conserved among species, which strengthen the ribosome assembly and prevent apoptosis triggered by cytochrome c (Cyt c). Our discovery opens a potential and novel paradigm of tRNA demethylase, which regulates biological functions via generation of tDRs.

N6-methyladenosine (m(6)A) methylation, which is modified by the METTL3/METTL14 complex, is a dominant internal modification in mammalian RNA and tightly linked to cancer progression. Here we reveal that METTL3-promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) are associated with expression and membrane localization of β-catenin (encoded by CTNNB1), as opposed to Wnt signaling activation in various types of cancer cells, including cervical, lung, and liver cancer. Specifically, METTL3 regulates the transcription, mRNA decay, translation, and subcellular localization of β-catenin. For CTNNB1 expression, METTL3 indirectly suppresses CTNNB1 transcription by stabilizing its transcription suppressor E2F1 mRNA； deposition of 5′UTR m(6)A in CTNNB1 promotes its decay in a content-dependent manner via YTHDF2 recognition; 5′UTR m(6)A in CTNNB1 suppresses its translation efficiency, whereas the global METTL3 level controls the canonical and non-canonical translation of CTNNB1, which is probably associated with the interaction between YTHDF1 and eIF4E1/eIF4E3. For β-catenin translocation, METTL3 represses membrane localization of β-catenin and its interaction with E-cadherin by downregulating c-Met kinase, leading to inhibition of cell motility. In vitro, in vivo, and clinical analyses confirm the essential role of β-catenin and its expression regulators in cancer cell dissemination. The findings not only expand our understanding of m(6)A modification and its roles in gene expression and subcellular localization of targets but also suggest that the METTL3/β-catenin axis might be a potential target to inhibit cancer metastasis.

Additional file 1: Fig. S1. The standard curve of 5′-tRF-GlyGCC quantification. Fig. S2. ALKBH3 is involved in the biogenesis of 5′-tRF-GlyGCC. Fig. S3. The nude mice (A) and BALB/c (B) mice bearing CRC cells xenografted tumor. Table S1. Background information of the Small RNA sequencing samples. Table S2. Background demographic of the study cohorts. Table S4. Relationship between the levels of 5′-tRF-GlyGCC and the clinicopathological variables in CRC patients. Table S5. Clinical diagnosis utility about various marker alone and their combination effects for CRC diagnosis.

Dysregulation of small non‐coding RNA (ncRNA) is associated with various human diseases including cancer. This study aimed to evaluate the circulating exosomal small RNAs including microRNAs (miRNAs) and P‑element‑induced wimpy testis (PIWI)‐interacting RNAs (piRNAs) as sensitive and specific non‐invasive biomarkers for gastric cancer (GC) diagnosis. Serum exosomal small RNA transcriptome was examined using unique molecular identifiers (UMI) small RNA sequencing. Dysregulated miRNAs and piRNAs were verified in 70 GC patients and 60 healthy controls (HC) by reverse transcription quantitative PCR. The expressions of miR‐1307‐3p, piR‐019308, piR‐004918 and piR‐018569 in serum exosomes were significantly increased in GC group as compared to those in HC group. Moreover, GC patients with metastasis had significantly higher expression levels of piR‐004918 and piR‐019308 than GC patients without metastasis. The area under the curve (AUC) for miR‐1307‐3p, piR‐019308, piR‐004918 and piR‐018569 in the GC group was 0.845, 0.820, 0.754 and 0.732, respectively. The combination of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 199 can improve the AUC of miR‐1307‐3p to 0.902 and piR‐019308 to 0.914 for GC diagnosis. In conclusion, our findings indicate that serum exosomal piRNAs are promising non‐invasive diagnostic biomarkers for GC patients and potential markers for monitoring metastasis.

Background Brain metastasis (BM) is one of the principal causes of mortality for lung cancer patients. While the molecular events that govern BM of lung cancer remain frustrating cloudy. Methods The miRNA expression profiles are checked in the paired human BM and primary lung cancer tissues. The effect of miR-143-3p on BM of lung cancer cells and its related mechanisms are investigated. Results miR-143-3p is upregulated in the paired BM tissues as compared with that in primary cancer tissues. It can increase the invasion capability of in vitro blood brain barrier (BBB) model and angiogenesis of lung cancer by targeting the three binding sites of 3’UTR of vasohibin-1 (VASH1) to inhibit its expression. Mechanistically, VASH1 can increase the ubiquitylation of VEGFA to trigger the proteasome mediated degradation, further, it can endow the tubulin depolymerization through detyrosination to increase the cell motility. m6A methyltransferase Mettl3 can increase the splicing of precursor miR-143-3p to facilitate its biogenesis. Moreover, miR-143-3p/VASH1 axis acts as adverse prognosis factors for in vivo progression and overall survival (OS) rate of lung cancer. Conclusions Our work implicates a causal role of the miR-143-3p/VASH1 axis in BM of lung cancers and suggests their critical roles in lung cancer pathogenesis.

Nowadays, risk factors of triple-negative breast cancer (TNBC) metastasis are not well identified. Our present study reveals that an industrial chemical, bisphenol S (BPS), can promote the migration, but not the proliferation, of TNBC cells in vitro. BPS activates YAP, a key effector of Hippo pathway, by inhibiting its phosphorylation, which promotes YAP nuclear accumulation and up-regulates its downstream genes such as CTGF and ANKRD1. Inhibition of YAP blocks the BPS-triggered cell migration and up-regulation of fibronectin (FN) and vimentin (Vim). BPS rapidly decreases the phosphorylation levels of LATS1 (Ser909) in TNBC cells, which regulates the activation and functions of YAP. Silencing LATS1/2 by siRNA increases BPS-induced dephosphorylation of YAP and extended the half-life of YAP protein. Inhibition of G protein-coupled estrogen receptor 1 (GPER) and its downstream PLCβ/PKC signals attenuate the effects of BPS-induced YAP dephosphorylation and CTGF up-regulation. Targeted inhibition of GPER/YAP inhibits BPS-induced migration of TNBC cells. Collectively, we reveal that GPER/Hippo-YAP signal is involved in BPS-induced migration of TNBC cells.

// Yuan Wang 1 , Guo-Hui Wan 1 , Ying-Min Wu 1 , Hong-Sheng Wang 1 , Hai-Fang Wang 1 , Ge Zhang 1 , Lin-Lin Lu 1 , Zi-Qian Li 1 , Ka-Ying Chan 1 , Yan Zhou 1 , Shao-Hui Cai 2 , Yi-Fei Qi 1 and Jun Du 1 1 Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China 2 Department of Pharmacology, School of Pharmaceutical Sciences, Jinan University, Guangzhou 510632, China Correspondence to: Jun Du, email: dujun@mail.sysu.edu.cn Keywords: drug resistant; HDAC inhibitor; JNJ26481585; AP-1; XIAP Received: June 21, 2017 Accepted: October 30, 2017 Epub: January 03, 2018 Published: March 06, 2018 ABSTRACT The underlying cause of treatment failure in many cancer patients is intrinsic and acquired resistance to chemotherapy. Recently, histone deacetylase (HDAC) inhibitors have developed into a promising cancer treatment. However, resistance mechanism induced by HDAC inhibitors remains largely unknown. Here we report that a HDAC inhibitor, JNJ-2648158 induced transcription of XIAP by activating AP-1 expression, which conferring resistance to chemotherapeutics. Our results showed that high expression of c-Fos caused by HDAC inhibitor promoted AP-1 formation during acquired resistance towards chemo-drugs, indicating an extremely poor clinical outcome in breast cancers and liver cancers. Our study reveals a novel regulatory mechanism towards chemo-drug resistance, and suggests that XIAP may serve as a potential therapeutic target in those chemo-resistant cancer cells.

Background Dysregulation of N6-methyladenosine (m6A) is associated with various human diseases including cancer. This study aimed to evaluate the level of m6A as a biomarker for gastric cancer (GC) diagnosis. Methods Peripheral blood samples were collected from 100 GC patients, 30 benign gastric disease (BGD) patients, and 75 healthy controls (HCs). Levels of m6A in total RNA and expression of m6A-related proteins were analyzed. Results The m6A levels in peripheral blood RNA were significantly increased in the GC group compared with those in the BGD or HC groups; moreover, levels increased with the progression and metastasis of GC and decreased in GC patients after surgery. The area under the curve (AUC) for m6A in the GC group was 0.929 (95% CI, 0.88–0.96), which is markedly greater than the AUCs for carcinoembryonic antigen (CEA; 0.694) and carbohydrate antigen 199 (CA199; 0.603). The combination of CEA and CA199 with m6A improved the AUC to 0.955 (95% CI, 0.91–0.98). The expressions of m6A demethylases ALKBH5 and FTO were significantly downregulated in the GC group compared with the HC group. Coculture with GC cells increased the m6A of RNA in promyelocytic (HL-60) and monocytic (THP-1) leukemia cells and nontumorigenic human peripheral blood B lymphocyte cells (PENG-EBV). Furthermore, a xenograft model enhanced the m6A in peripheral blood RNA of mice. Accordingly, expressions of ALKBH5 and FTO were decreased both in vitro and in vivo. Conclusions Level of m6A in peripheral blood RNA is a promising noninvasive diagnostic biomarker for GC patients.

N6-Methyladenosine (m6A) modification has been implicated in the progression of several cancers. We reveal that during epithelial-mesenchymal transition (EMT), one important step for cancer cell metastasis, m6A modification of mRNAs increases in cancer cells. Deletion of methyltransferase-like 3 (METTL3) down-regulates m6A, impairs the migration, invasion and EMT of cancer cells both in vitro and in vivo. m6A-sequencing and functional studies confirm that Snail, a key transcription factor of EMT, is involved in m6A-regulated EMT. m6A in Snail CDS, but not 3’UTR, triggers polysome-mediated translation of Snail mRNA in cancer cells. Loss and gain functional studies confirm that YTHDF1 mediates m6A-increased translation of Snail mRNA. Moreover, the upregulation of METTL3 and YTHDF1 act as adverse prognosis factors for overall survival (OS) rate of liver cancer patients. Our study highlights the critical roles of m6A on regulation of EMT in cancer cells and translation of Snail during this process., RNA m6A methylation is known to be dysregulated in many cancers. Here, the authors show that m6A methylation of Snail mRNA regulates its translation with potential effects on epithelial mesenchymal transition.

Background Long noncoding RNAs (lncRNAs) have emerged as critical players in cancer progression, but their functions in colorectal cancer (CRC) metastasis have not been systematically clarified. Methods lncRNA expression profiles in matched normal and CRC tissue were checked using microarray analysis. The biological roles of a novel lncRNA, namely RP11-138 J23.1 (RP11), in development of CRC were checked both in vitro and in vivo. Its association with clinical progression of CRC was further analyzed. Results RP11 was highly expressed in CRC tissues, and its expression increased with CRC stage in patients. RP11 positively regulated the migration, invasion and epithelial mesenchymal transition (EMT) of CRC cells in vitro and enhanced liver metastasis in vivo. Post-translational upregulation of Zeb1, an EMT-related transcription factor, was essential for RP11-induced cell dissemination. Mechanistically, the RP11/hnRNPA2B1/mRNA complex accelerated the mRNA degradation of two E3 ligases, Siah1 and Fbxo45, and subsequently prevented the proteasomal degradation of Zeb1. m6A methylation was involved in the upregulation of RP11 by increasing its nuclear accumulation. Clinical analysis showed that m6A can regulate the expression of RP11, further, RP11 regulated Siah1-Fbxo45/Zeb1 was involved in the development of CRC. Conclusions m6A-induced lncRNA RP11 can trigger the dissemination of CRC cells via post-translational upregulation of Zeb1. Considering the high and specific levels of RP11 in CRC tissues, our present study paves the way for further investigations of RP11 as a predictive biomarker or therapeutic target for CRC.

Additional file 1: Figure S1. miR-143-3p is correlated with the BM and progression of lung cancer. Figure S2. The effects of miRNAs on the malignancy of lung cancer cells. Figure S3. VASH1 mediates miR143 induced cell dissemination and angiogenesis. Figure S4. VASH1 mediates miR-143-3p induced angiogenesis via destabilization of VEGFA. Figure S5. VASH1 mediates miR-143-3p induced reprogramming of microtubules. Figure S6. m6A regulates the expression of miR-143-3p in lung cancer cells. Figure S7. The miR-143-3p/VASH axis and in vivo BM of lung cancer. Table S1. Clinical characteristics of 6 lung cancer patients with BM. Table S2. Clinical characteristics of lung cancer patients with or without BM. Table S3. The potential targets of miR-143-3p predicted by five different web-based databases.

// Ying-Min Wu 1, * , Zhuo-Jia Chen 2, * , Guan-Min Jiang 3 , Kun-Shui Zhang 4 , Qiao Liu 1 , Shu-Wei Liang 1 , Yan Zhou 1 , Hong-Bin Huang 2 , Jun Du 1 , Hong-Sheng Wang 1 1 Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China 2 Department of Pharmacy, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China 3 Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China 4 Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China * These author contributed equally to this work Correspondence to: Hong-Sheng Wang, e-mail: whongsh@mail.sysu.edu.cn , hongshengwang@foxmail.com Jun Du, e-mail: dujun@mail.sysu.edu.cn Keywords: ERRα, XCT-790, TNBC, ROS, growth arrest Received: September 25, 2015 Accepted: January 23, 2016 Published: February 09, 2016 ABSTRACT There is an urgent clinical need for targeted therapy approaches for triple-negative breast cancer (TNBC) patients. Increasing evidences suggested that the expression of estrogen-related receptor alpha (ERRα) was correlate with unfavorable clinical outcomes of breast cancer patients. We here show that inhibition of ERRα by its inverse agonist XCT-790 can suppress the proliferation, decrease G2/M phases, and induce mitochondrial-related apoptosis of TNBC cells. XCT-790 elevates the proteins related to endoplasmic reticulum (ER) stress such as ATF4/6, XBT-1 and CHOP. It also increases the expression of growth inhibition related proteins such as p53 and p21. Further, XCT-790 can increase the generation of reactive oxygen species (ROS) in TNBC cells mainly through inhibition of SOD1/2. While ROS scavenger NAC abolishes XCT-790 induced ER-stress and growth arrest. XCT-790 treatment can rapidly activate the signal molecules including ERK1/2, p38-MAPK, JNK, Akt, p65, and IκBα, while NAC attenuates effects of XCT-790 induced phosphorylation of ERK1/2, p38-MAPK and Akt. Further, the inhibitors of ERK1/2, JNK, Akt, and NF-κB attenuate XCT-790 induced ROS generation. These data suggest that AKT/ROS and ERK/ROS positive feedback loops, NF-κB/ROS, and ROS/p38-MAPK, are activated in XCT-790 treated TNBC cells. In vivo experiments show that XCT-790 significantly suppresses the growth of MDA-MB-231 xenograft tumors, which is associated with up regulation of p53, p21, ER-stress related proteins while down regulation of bcl-2. The present discovery makes XCT-790 a promising candidate drug and lays the foundation for future development of ERRα-based therapies for TNBC patients.

Background Long noncoding RNAs (lncRNAs) have emerged as critical players in cancer progression, but their functions in colorectal cancer (CRC) metastasis have not been systematically clarified. Methods lncRNA expression profiles in matched normal and CRC tissue were checked using microarray analysis. The biological roles of a novel lncRNA, namely RP11-138 J23.1 (RP11), in development of CRC were checked both in vitro and in vivo. Its association with clinical progression of CRC was further analyzed. Results RP11 was highly expressed in CRC tissues, and its expression increased with CRC stage in patients. RP11 positively regulated the migration, invasion and epithelial mesenchymal transition (EMT) of CRC cells in vitro and enhanced liver metastasis in vivo. Post-translational upregulation of Zeb1, an EMT-related transcription factor, was essential for RP11-induced cell dissemination. Mechanistically, the RP11/hnRNPA2B1/mRNA complex accelerated the mRNA degradation of two E3 ligases, Siah1 and Fbxo45, and subsequently prevented the proteasomal degradation of Zeb1. m6A methylation was involved in the upregulation of RP11 by increasing its nuclear accumulation. Clinical analysis showed that m6A can regulate the expression of RP11, further, RP11 regulated Siah1-Fbxo45/Zeb1 was involved in the development of CRC. Conclusions m6A-induced lncRNA RP11 can trigger the dissemination of CRC cells via post-translational upregulation of Zeb1. Considering the high and specific levels of RP11 in CRC tissues, our present study paves the way for further investigations of RP11 as a predictive biomarker or therapeutic target for CRC. Electronic supplementary material The online version of this article (10.1186/s12943-019-1014-2) contains supplementary material, which is available to authorized users.

Triple-negative breast cancer (TNBC) shows highly aggressive clinical behaviors and poor prognosis compared to other breast cancer subtypes. Histone deacetylases (HDACs) can regulate the progression of various cancers, but the role of HDAC8 in TNBC remains unexplored. Here, we found that HDAC8 enhanced the in vitro migration abilities of breast cancer cells. Targeted inhibition of HDAC8 via si-HDAC8 and its selective inhibitor PCI34051 could suppress the migration of cells. In TNBC cells, HDAC8 stabilized the expression and increased the nuclear localization of YAP, a major downstream effector of Hippo pathway. While silencing YAP could attenuate HDAC8 triggered migration of TNBC cells. Mechanistically, HDAC8 suppressed the phosphorylation of YAPSer127, which was related to its cytoplasmic sequestration degradation. Our data revealed that HDAC8 could trigger the migration of TNBC cells via regulation of Hippo-YAP signals, suggesting that HDAC8 might be a potential target for TNBC therapy.

There is an urgent need to investigate the potential targeted therapy approach for triple-negative breast cancer (TNBC). Our present study reveals that histone deacetylase inhibitors (HDACIs) suberoyl anilide hydroxamic acid (SAHA) and sodium butyrate (NaB) significantly inhibit cell proliferation, arrest cell cycle at G0/G1 phase, and induce mitochondrial related apoptosis of TNBC cells. Further, SAHA and NaB decrease the phosphorylation, protein and mRNA levels of mutant p53 (mtp53) in TNBC cells. While SAHA or NaB has no similar inhibition effect on wild type p53 (wtp53). The inhibition apparently occurs at the level of transcription because the down regulation of precursor p53 transcription is much more rapid (less than 2 h) and sharp than that of mature p53. The knockdown of HDAC8, while not HDAC6, inhibits the transcription of mtp53 in TNBC cells. The luciferase assay and ChIP analysis reveal that both SAHA and NaB can reduce the binding of transcription factor Yin Yang 1 (YY1) with the − 102 to − 96 position of human p53 promoter. Knockdown of YY1 also significantly inhibits the transcription of mtp53 in TNBC cells. Further, SAHA and NaB can inhibit the association of HDAC8 and YY1, increase acetylation of residues 170–200 of YY1, then decrease its transcription activities, and finally suppress YY1 induced p53 transcription. Together, our data establish that SAHA and NaB can be considered as drug candidates for TNBC patients, and HDAC8/YY1/mtp53 signals act as an important target for TNBC treatment.

A new catalyst consisted of polyaniline, platinum and hydrogen molybdenum bronze (H x MoO 3 ) is prepared and its catalytic activity and stability for the oxidation of methanol are studied by using cyclic voltammetry and chronoamperometry. A comparison of the catalysts with and without polyaniline was made. The electrocatalytic activity of platinum toward the oxidation of methanol is improved by the modification of H x MoO 3 . However, this modification is degraded due to the instability of H x MoO 3 . The catalytic current for the methanol oxidation on Pt–H x MoO 3 decays with time and becomes as low as that on platinum after potentiostat at 0.6 V (vs. SCE) for 1800 s. Polyaniline improves the stability of H x MoO 3 as well as catalytic activity of Pt–H x MoO 3 toward the methanol oxidation. The catalytic current during cycling voltammetry for the methanol oxidation on Pt–H x MoO 3 is significantly improved by the modification of polyaniline. It is 8.65 × 10 −4 A for Pt–H x MoO 3 electrode, but 2.04 × 10 −2 A for Polyaniline–Pt–H x MoO 3 at 0.45 V (vs. SCE). Unlike the behavior of Pt–H x MoO 3 catalyst, the current responses on polyaniline–Pt–H x MoO 3 catalyst to a potential step decay with time very slowly.

Constructing support systems for market opportunity discovery in order to make it easier to identify and seize market opportunities has become an in-depth demand for many enterprises. We aim at the unsolved problems such as non-precision and semi-structured data sources, complex relationships, flexible structure, process support, et cetera, and redefine market opportunities as well as market opportunity discovery (MOD) from a cognitive point of view, and then propose a hyper graph model for MOD. Based on the model, we design some MOD decision support methods as pattern recognition, path analysis, and information absorption, after exploring the mechanism of prior knowledge in MOD process. We also put our model into the practice of commercial banks' MOD activities and illustrate its validity and advantages.

Prior knowledge serves as some relational patterns assisting to recognize connections between apparently independent events and trends, which is the main way of prior knowledge working in opportunity discovery process. However, these relational patterns usually are latent, imprecise and semi-structured, are difficult to be formal description. This results in restriction of current methods in Artificial Intelligence to support opportunity discovery. To solve this problem, a hypergraph model is proposed to describe and construct the relational patterns, within which discrete vertices and latent relations are obtained by text association mining. A case of Chinapsilas commercial bankpsilas restructure is used to describe the application of it. The result shows that the model has abilities of visualization and simulation for the components and patterns mined from texts, as well as supporting the opportunity discovery. The further research of this model is mentioned in the end of paper.

There is an urgent clinical need for safe and effective treatment agents and therapy targets for estrogen receptor negative (ER−) breast cancer. G protein-coupled receptor 30 (GPR30), which mediates non-genomic signaling of estrogen to regulate cell growth, is highly expressed in ER− breast cancer cells. We here showed that activation of GPR30 by the receptor-specific agonist G-1 inhibited the growth of ER− breast cancer cells in vitro. Treatment of ER− breast cancer cells with G-1 resulted in G2/M-phase arrest, downregulation of G2-checkpoint regulator cyclin B, and induction of mitochondrial-related apoptosis. The G-1 treatment increased expression of p53 and its phosphorylation levels at Serine 15, promoted its nuclear translocation, and inhibited its ubiquitylation, which mediated the growth arrest effects on cell proliferation. Further, the G-1 induced sustained activation and nuclear translocation of ERK1/2, which was mediated by GPR30/epidermal growth factor receptor (EGFR) signals, also mediated its inhibition effects of G-1. With extensive use of siRNA-knockdown experiments and inhibitors, we found that upregulation of p21 by the cross-talk of GPR30/EGFR and p53 was also involved in G-1-induced cell growth arrest. In vivo experiments showed that G-1 treatment significantly suppressed the growth of SkBr3 xenograft tumors and increased the survival rate, associated with proliferation suppression and upregulation of p53, p21 while downregulation of cyclin B. The discovery of multiple signal pathways mediated the suppression effects of G-1 makes it a promising candidate drug and lays the foundation for future development of GPR30-based therapies for ER− breast cancer treatment.