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Our previous study has reported that metastasis-associated protein 2 (MTA2) plays essential roles in tumorigenesis and aggressiveness of gastric cancer (GC). However, the underlying molecular mechanisms of MTA2-mediated GC and its upstream regulation mechanism remain elusive. In this study, we identified a novel circular RNA (circRNA) generated from the MTA2 gene (circMTA2) as a crucial regulator in GC progression. CircMTA2 was highly expressed in GC tissues and cell lines, and circMTA2 promoted the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circMTA2 interacted with ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) to restrain MTA2 ubiquitination and stabilize MTA2 protein expression, thereby facilitating tumor progression. Moreover, circMTA2 was mainly encapsulated and transported by exosomes to promote GC cell progression. Taken together, these findings uncover that circMTA2 suppresses MTA2 degradation by interacting with UCHL3, thereby promoting GC progression. In conclusion, we identified a cancer-promoting axis (circMTA2/UCHL3/MTA2) in GC progression, which paves the way for us to design and synthesize targeted inhibitors as well as combination therapies. [ABSTRACT FROM AUTHOR]

The nucleosome remodeling and histone deacetylase (NuRD) complex physically associates with BCL11B to regulate murine T‐cell development. However, the function of NuRD complex in mature T cells remains unclear. Here, we characterize the fate and metabolism of human T cells in which key subunits of the NuRD complex or BCL11B are ablated. BCL11B and the NuRD complex bind to each other and repress natural killer (NK)‐cell fate in T cells. In addition, T cells upregulate the NK cell‐associated receptors and transcription factors, lyse NK‐cell targets, and are reprogrammed into NK‐like cells (ITNKs) upon deletion of MTA2, MBD2, CHD4, or BCL11B. ITNKs increase OPA1 expression and exhibit characteristically elongated mitochondria with augmented oxidative phosphorylation (OXPHOS) activity. OPA1‐mediated elevated OXPHOS enhances cellular acetyl‐CoA levels, thereby promoting the reprogramming efficiency and antitumor effects of ITNKs via regulating H3K27 acetylation at specific targets. In conclusion, our findings demonstrate that the NuRD complex and BCL11B cooperatively maintain T‐cell fate directly by repressing NK cell‐associated transcription and indirectly through a metabolic‐epigenetic axis, providing strategies to improve the reprogramming efficiency and antitumor effects of ITNKs. Synopsis: While BCL11b is known to bind the NuRD complex and be required for T cell development, the function of these factors in mature T cells has so far been unclear. This work demonstrates how the NuRD complex and BCL11B together maintain T‐cells from reprogramming into NK cells. T cells are reprogrammed into NK‐like cells upon deletion of MTA2, MBD2, or CHD4.BCL11B associates with the NuRD complex to repress OPA1 expression in T cells.OPA1‐mediated mitochondrial fusion facilitates ITNK reprogramming and cytotoxicity by increasing OXPHOS.Acetyl‐CoA elevated by OXPHOS promotes NK‐cell‐associated genes expression and antitumor effects in ITNKs by regulating H3K27 acetylation. [ABSTRACT FROM AUTHOR]

Purpose: To study the function, regulation, and potential clinical use of mta2 gene in carcinoma of the bladder. Methods: Viral vector and si-mta2 were transfected into both T24 and EJ bladder cancer cells, for induction of overexpression and knockdown of metastasis-associated gene 2 (mta2), respectively. In vitro invasiveness and migratory potential of cell lines were assayed using Matrigel and Transwell procedures, respectively, under the two mta2 expression conditions. Results: Transwell migration data revealed that overexpressed mta2 protein significantly enhanced the migratory capacity of T24 bladder cancer cell line, while knockdown of mta2 significantly reduced the migration of EJ bladder cancer cell line (p < 0.01). Matrigel invasion assay showed that overexpression of mta2 protein significantly enhanced the invasive potential of T24 bladder cancer cell line, but knockdown of mta2 significantly (p < 0.01) reduced the invasive capacity of EJ bladder cancer cell line. There was a lower amount of E-cadherin protein in T24 bladder cancer cell line overexpressing mta2 than in cd511b-transfected and un-transfected cells, but N-cadherin protein level was significantly higher. Furthermore, there was a significantly higher amount of E-cadherin protein expression in EJ bladder cancer cell line with mta2 knockdown than in si-NC transfection and un-transfected cells (p < 0.01). Conclusion: Knockdown of mta2 inhibits the proliferation, migration and invasion of bladder cancer cell lines through a mechanism related to the inhibition of epithelial-mesenchymal transition-related process proteins. [ABSTRACT FROM AUTHOR]

Background: Metastasis-associated protein 2 (MTA2) is a member of the metastasis-associated transcriptional regulator family and is a core component of the nucleosome remodeling and histone deacetylation complex. Despite growing evidence that MTA2 plays a crucial role in the tumorigenesis of certain cancers, no systematic pan-cancer analysis of MTA2 is available to date. Therefore, the aim of our study is to explore the prognostic value of MTA2 in 33 cancer types and to investigate its potential immune function. Methods: by comprehensive use of databases from TCGA, GTEx, GEO, UCSC xena, cBioPortal, comPPI, GeneMANIA, TCIA, MSigDB, and PDB, we applied various bioinformatics approaches to investigate the potential role of MTA2, including analyzing the association of MTA2 with MSI, prognosis, gene mutation, and immune cell infiltration in different tumors. We constructed a nomogram in TCGA-LIHC, performed single-cell sequencing (scRNA-seq) analysis of MTA2 in hepatocellular carcinoma (HCC), and screened drugs for the treatment of HCC. Finally, immunohistochemical experiments were performed to verify the expression and prognostic value of MTA2 in HCC. In vitro experiments were employed to observe the growth inhibition effects of MK-886 on the HCC cell line HepG2. Results: The results suggested that MTA2 was highly expressed in most cancers, and MTA2 expression was associated with the prognosis of different cancers. In addition, MTA2 expression was associated with Tumor Mutation Burden (TMB) in 12 cancer types and MSI in 8 cancer types. Immunoassays indicated that MTA2 positively correlated with activated memory CD4 T cells and M0 macrophage infiltration levels in HCC. ScRNA-seq analysis based on the GEO dataset discovered that MTA2 was significantly expressed in T cells in HCC. Finally, the eXtreme Sum (Xsum) algorithm was used to screen the antitumor drug MK-886, and the molecular docking technique was utilized to reveal the binding capacity between MK-886 and the MTA2 protein. The results demonstrated excellent binding sites between them, which bind to each other through Π-alkyl and alkyl interaction forces. An immunohistochemistry experiment showed that MTA2 protein was highly expressed in HCC, and high MTA2 expression was associated with poor survival in HCC patients. MK-886 significantly inhibited the proliferation and induced cell death of HepG2 cells in a dose-dependent manner. Conclusions: Our study demonstrated that MTA2 plays crucial roles in tumor progression and tumor immunity, and it could be used as a prognostic marker for various malignancies. MK-886 might be a powerful drug for HCC. [ABSTRACT FROM AUTHOR]

Objective: Angiogenesis plays a vital role in tumor growth and metastasis. Here, we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A (VEGFA ) at the transcriptional level to treat triple-negative breast cancer (TNBC). Methods: We used a cell-based seryl tRNA synthetase (SerRS) promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS, a potent transcriptional repressor of VEGFA. The levels of SerRS and VEGFA were examined by quantitative RT-PCR (qRT-PCR), western blotting, and/or ELISAs in TNBC cells after candidate molecule administration. Zebrafish, the Matrigel plug angiogenesis assay in mice, the TNBC allograft, and xenograft mouse models were used to evaluate the in vivo anti-angiogenic and anti-cancer activities. Furthermore, the potential direct targets of the candidates were identified by proteomics and biochemical studies. Results: We found the most active compound was 3-(4-methoxyphenyl) quinolin-4(1H)-one (MEQ), an isoflavone derivative. In TNBC cells, MEQ treatment resulted in increased SerRS mRNA (P < 0.001) and protein levels and downregulated VEGFA production. Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ. MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice, resulting in inhibited tumor growth and prolonged overall survival (P < 0.05). Finally, we found that MEQ regulated SerRS transcription by interacting with MTA2 (Metastasis Associated 1 Family Member 2). Conclusions: Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target, and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.

MTA2 is involved in tumor proliferation and metastasis. However, the role of MTA2 in cervical cancer thus far has not been identified. In this study, we report that elevated expression of MTA2 negatively correlates with Kallikrein-10 (KLK10) expression and poor prognosis of cervical cancer patients. Knockdown of MTA2 substantially inhibited tumor cell migration and invasion, and it enhanced KLK10 expression of the cervical cancer cells in vitro and in vivo. Functionally, shMTA2-mediated suppression of cell mobility was significantly restored by knockdown of KLK10. We also found that Sp1 (transcription factor specificity protein 1) is critical for shMTA2-induced transcriptional upregulation of KLK10 and subsequent biological functions. Furthermore, we found that the expression of miR-7 is elevated by MTA2 silencing and then by direct inhibition of Sp1 expression. Knockdown of Sp1 additively enhanced KLK10 expression in MTA2-knocked down cervical cancer cells, suggesting that the miR-7/Sp1 axis acts as an effector of MTA2 to impact KLK10 levels and mobility of cervical cancer cells. Taken together, our findings provide new insights into the physiological relationship between MTA2 and KLK10 via regulating the miR-7/Sp1 axis, and they provide a potential therapeutic target in cervical cancer.

The relationship between metastasis-associated protein 2 (MTA2) overexpression and tumor growth and metastasis has been extensively studied in a variety of tumor cells but not in human osteosarcoma cells. This study aims to elucidate the clinical significance, underlying molecular mechanisms, and biological functions of MTA2 in human osteosarcoma in vitro and in vivo . Our results show that MTA2 was elevated in osteosarcoma cell lines and osteosarcoma tissues and was associated with tumor stage and overall survival of osteosarcoma patients. Knockdown of MTA2 inhibited osteosarcoma cell migration and invasion by reducing the expression of urokinase-type plasminogen activator (uPA). Bioinformatic analysis demonstrated that high levels of uPA in human osteosarcoma tissues correlated positively with MTA2 expression. Furthermore, treatment with recombinant human uPA (Rh-uPA) caused significant restoration of OS cell migration and invasion in MTA2 knockdown osteosarcoma cells. We found that ERK1/2 depletion increased the expression of uPA, facilitating osteosarcoma cell migration and invasion. Finally, MTA2 depletion significantly reduced tumor metastasis and the formation of lung nodules in vivo . Overall, our study suggests that MTA2 knockdown suppresses osteosarcoma cell metastasis by decreasing uPA expression via ERK signaling. This finding provides new insight into potential treatment strategies against osteosarcoma metastasis by targeting MTA2.

Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib selectively kills cancer cells with BRCA-deficiency and is approved for BRCA-mutated breast, ovarian and pancreatic cancers by FDA. However, phase III study of olaparib failed to show a significant improvement in overall survival in patients with gastric cancer (GC). To discover an effective biomarker for GC patient-selection in olaparib treatment, we analyzed proteomic profiling of 12 GC cell lines. MTA2 was identified to confer sensitivity to olaparib by aggravating olaparib-induced replication stress in cancer cells. Mechanistically, we applied Cleavage Under Targets and Tagmentation assay to find that MTA2 proteins preferentially bind regions of replication origin-associated DNA sequences, which could be enhanced by olaparib treatment. Furthermore, MTA2 was validated here to render cancer cells susceptible to combination of olaparib with ATR inhibitor AZD6738. In general, our study identified MTA2 as a potential biomarker for olaparib sensitivity by aggravating olaparib-induced replication stress.

Substantial evidence supports the hypothesis that enhancers are critical regulators of cell-type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of LIM domain-binding protein 1 (LDB1)/cofactor of LIM homeodomain protein 2/nuclear LIM interactor, interacting with the enhancer-binding protein achaete-scute complex homolog 1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells. LDB1-mediated enhancer:promoter looping appears to be required for both activation and repression of these target genes. Although LDB1-dependent activated genes are regulated at the level of transcriptional initiation, the LDB1-dependent repressed transcription units appear to be regulated primarily at the level of promoter pausing, with LDB1 regulating recruitment of metastasis-associated 1 family, member 2, a component of the nucleosome remodeling deacetylase complex, on these negative enhancers, required for the repressive enhancer function. These results indicate that LDB1-dependent looping events can deliver repressive cargo to cognate promoters to mediate promoter pausing events in a pituitary cell type.

Metastasis‐associated protein 2 (MTA2) is frequently amplified in many types of cancers; however, the role and underlying molecular mechanism of MTA2 in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we reported that MTA2 is highly expressed in ESCC tissue and cells, and is closely related to the malignant characteristics and poor prognosis of patients with ESCC. Through in vitro and in vivo experiments, we demonstrated that MTA2 significantly promoted ESCC growth, metastasis, and epithelial‐mesenchymal transition (EMT) progression. This integrative analysis combined with expression microarray showed that MTA2 could interact with eukaryotic initiation factor 4E (EIF4E), which positively regulates the expression of Twist, known as a master regulator of EMT. Moreover, the results of chromatin immunoprecipitation revealed that MTA2 was recruited to the E‐cadherin promoter by Twist, which reduced the acetylation level of the promoter region and thus inhibited expression of E‐cadherin, and subsequently promoted the aggressive progression of ESCC. Collectively, our study provided novel evidence that MTA2 plays an aggressive role in ESCC metastasis by a novel EIF4E‐Twist positive feedback loop, which may provide a potential therapeutic target for the management of ESCC. [ABSTRACT FROM AUTHOR]

Abstract Background As the first member of the metastasis-associated protein (MTA) family, MTA1 and another MTA family member, MTA2, have both been reported to promote breast cancer progression and metastasis. However, the difference and relationship between MTA1 and MTA2 have not been fully elucidated. Methods Transwell assays were used to assess the roles of MTA1 and MTA2 in the metastasis of ZR-75-30 luminal B breast cancer cells in vitro. Immunoblotting and qRT-PCR were used to evaluate the effect of MTA1 overexpression on MTA2. Proteases that cleave MTA2 were predicted using an online web server. The role of neutrophil elastase (NE) in MTA1 overexpression-induced MTA2 downregulation was confirmed by specific inhibitor treatment, knockdown, overexpression and immunocytochemistry, and NE cleavage sites in MTA2 were confirmed by MTA2 truncation and mutation. The effect of MTA1 overexpression on the intrinsic inhibitor of NE, elafin, was detected by qRT-PCR, immunoblotting and treatment with inhibitors. Results MTA1 overexpression inhibited, while MTA2 promoted the metastasis of ZR-75-30 cells in vitro. MTA1 overexpression downregulated MTA2 expression at the protein level rather than the mRNA level. NE was predicted to cleave MTA2 and was responsible for MTA1 overexpression-induced MTA2 degradation. NE was found to cleave MTA2 in the C-terminus at the 486, 497, 542, 583 and 621 sites. MTA1 overexpression activated NE by downregulating elafin in a histone deacetylase- and DNA methyltransferase-dependent manner. Conclusions MTA1 and MTA2 play opposing roles in the metastasis of ZR-75-30 luminal B breast cancer cells in vitro. MTA1 downregulates MTA2 at the protein level by epigenetically repressing the expression of elafin and releasing the inhibition of neutrophil elastase, which cleaves MTA2 in the C-terminus at multiple specific sites.

Abstract Background MicroRNAs deregulation are common in human tumor progression. miR-1236-3p has been reported to function as tumor suppressor microRNA in various malignancies. The aim of this study was to demonstrate the downregulated expression of miR-1236-3p in gastric cancer (GC) tissues and cell lines, and clarify its biological function in GC. Methods Real-time polymerase chain reaction was used to measure the mRNA level of miR-1236-3p in GC. Dual luciferase assay was used to demonstrate that MTA2 was one of the candidate target genes of miR-1236-3p. Western blots were utilized to detect the protein levels. Cell function assays were also performed to determine the function of miR-1236-3p in GC. Results miR-1236-3p expression, which was associated with lymph node metastasis, differentiation and clinical stage, was significantly reduced in GC tissues and cell lines. miR-1236-3p over-expression could inhibit GC cell proliferation, migration and invasion, and inhibition of miR-1236-3p expression had opposite effects. Furthermore, we demonstrated that MTA2 was a candidate target of miR-1236-3p, and miR-1236-3p over-expression significantly inhibited the process of epithelial–mesenchymal transition. We also found that miR-1236-3p could suppress the PI3K/Akt signaling pathway in GC cells. Conclusions Our results suggest that miR-1236-3p functions as a tumor suppressor in GC and could be a promising therapeutic target for GC.

Background: The overexpression of metastasis-associated protein 2 (MTA2) contributes to human tumor progression and metastasis in various tumor cells. However, the role of MTA2 in human oral cancer progression remains unknown.Materials and Methods: MTA2 expression in human oral tumor tissues and cell lines was measured by immunohistochemistry and Western blotting. Cell proliferation and cell cycle were analyzed using MTT assay and flow cytometry. The effects of MTA2 on oral cell migration and invasion were investigated using migration and invasion assays. The expression of MTA2, p-cofilin-1, and MTA2-induced LC3-II levels were measured using Western blotting and an immunofluorescence assay.Results: Based on the human oral cancer tissue array and TCGA database, we found that MTA2 was increased in oral cancer tissues than in non-tumor oral tissues (P < .01). Moreover, MTA2 is significantly associated with tumor grade (P < .01) and the overall survival rate of patients with grade III tumor (P < .05). MTA2 expression in oral cancer cells was markedly higher than that in normal oral cells. Cell proliferation and cell cycle were not significantly changed in the cells inhibited by MTA2. MTA2 knockdown can inhibit cell migration and invasion of human oral cancer cells. Furthermore, we suggest that MTA2 inhibition enhances p-cofilin and LC3-II expression, and the knockdown of LC3-II expression in cells inhibited by MTA2 had the opposite effect.Conclusion: These results indicate that MTA2 may serve as a candidate prognostic biomarker and that targeting autophagy is a potential therapeutic strategy for treating human oral cancer. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) has a poorer outcome compared with that of other subtypes of breast cancer, and the discovery of dysregulated microRNA (miRNA) and their role in tumor progression has provided a new avenue for elucidating the mechanism involved in TNBC. Previous studies have revealed that aberrant expression of miRNA-589 (miR-589) was frequently observed in various types of cancer. However, the expression and function of miR-589 in TNBC has not been well illustrated. In the present study, the expression level of miR-589 was explored in TNBC tissues and TNBC cell lines by quantitative polymerase chain reaction (qPCR). The results revealed that the expression of miR-589 was decreased in TNBC tissues and cell lines compared with that in normal tissues and breast cell lines. Furthermore, miR-589 overexpression decreased the TNBC cell proliferation, migration and invasion, whereas miR-589 silencing generated the opposite results in vitro. Bioinformatic algorithms predicted a direct target site for miR-589 in the 3′-untranslated region of metastasis-associated protein 2 (MTA2), which was confirmed with a dual-luciferase reporter assay and western blot analysis. Results of the qPCR and western blot analysis illustrated that miR-589 negatively regulated MTA2 expression with regard to mRNA and protein levels in the TNBC cell lines. MTA2 silencing reversed the promotion function of miR-589 inhibitor in the TNBC cell line. Finally, miR-589 could inhibit the process of epithelial-mesenchymal transition via MTA2. In summary, the present study revealed the biological function and molecular mechanism of miR-589 in the progression of TNBC. MiR-589 inhibition in the progression of TNBC may be a potential therapeutic target for TNBC. [ABSTRACT FROM AUTHOR]

Abstract: Metastasis‐associated protein 2 (MTA2) is overexpressed in certain malignancies, and plays important roles in tumour metastasis and progression. The present study highlights the function of MTA2 in pancreatic carcinoma through its role as a deacetylator of hypoxia‐inducible factor‐1α (HIF‐1α) and a cotranscriptional factor for E‐cadherin expression. We found that overexpression of MTA2 promoted, and knockdown of MTA2 inhibited, the invasion and proliferation of pancreatic carcinoma cells both in vitro and in xenograft models in vivo. We also found that MTA2 is transcriptionally upregulated by HIF‐1α through a hypoxia response element (HRE) of the MTA2 promoter in response to hypoxia. Reciprocally, MTA2 deacetylates HIF‐1α and enhances its stability through interacting with histone deacetylase 1 (HDAC1). Consequently, HIF‐1α recruits MTA2 and HDAC1 to the HRE of the E‐cadherin promoter, by which E‐cadherin transcription is repressed. In agreement with these experimental results, MTA2 is positively associated with HIF‐1α, but inversely correlated with E‐cadherin, in pancreatic carcinoma samples. Moreover, data from The Cancer Genome Atlas on 172 pancreatic carcinomas indicate an association between high expression of MTA2 and short overall survival. Taken together, our study identifies MTA2 as a critical hub and potential therapeutic target to inhibit the progression and metastasis of pancreatic carcinoma. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background The sensitivities and specificities of biomarkers for gastric cancer are insufficient for clinical detection, and new diagnostics are therefore urgently required. Methods A discovery set of gastric cancer tissues was labeled with iTRAQ reagents, separated using SCX chromatography, and identified using LC-ESI-MS/MS. A validation set of gastric cancer tissues was used to confirm the expression levels of potential markers. Results The present study detected metastasis-associated protein 2 (MTA2) and Histone deacetylases 1 (HDAC1) proteins that were overexpressed in gastric cancer tissues compared with that in adjacent gastric tissue. The sensitivity and specificity of MTA2 in detecting 76 cases gastric cancers were 57.9% (95% CI: 46.5%–69.3%) and 55.3% (95% CI: 43.8%–66.7%), respectively. The sensitivity and specificity of HDAC1 were 61.8% (95% CI: 50.7%–73%) and 63.2% (95% CI: 52.1%–74.3%), respectively. The co-expression of MTA2 and HDAC1 in gastric cancer achieved 65.3% sensitivity (95% CI: 51.5%–79.1%) and 65.2% specificity (95% CI: 50.9%–79.5%), which was strongly associated with lymph node metastasis and TNM staging. Conclusion The present findings indicated a tight correlation between the MTA2 and HDAC1 expression level and lymph node metastasis and TNM staging in gastric cancers. Therefore, MTA2 and HDAC1 might be predictors of lymph node metastasis phenotype and possible target molecule for anticancer drug design in human gastric cancer. [ABSTRACT FROM AUTHOR]

Background and objective It has been proven that MTA2 was expressed in many tumor cell lines and was correlated with tumor invasion and metastasis. The aim of this study is to investigate the expression of MTA2 protein in non-small cell lung cancer (NSCLC) and to explore the relationship between the expression of MTA2 and the pathological features. Methods The expression of MTA2 protein in 110 cases of NSCLC and 34 cases corresponding lung tissues was detected with immunohistochemistry method. The relationship between the expression of MTA2 and the pathological features in NSCLC was analyzed statistically. Results There was no expression of MTA2 protein in cancer collateral branch trachea epithelial and alveolar epithelial, but there was some expression in partial NSCLC. The positive rate of MTA2 was 58.18% (64/110) in 110 NSCLC cases. The expression of MTA2 had negative correlation with differentiation degree of NSCLC but had positive correlation with clinical stage and lymph node metastasis (P < 0.05), moreover, it had no obvious correlation with age, gender and pathological type (P > 0.05). Conclusion There was some expression of MTA2 in partial NSCLC and it was correlated with differentiation degree, clinical stage and lymph node metastasis. The results show that the occurrence and development of lung cancer may be related with MTA2. MTA2 may act as a new symbol and target in the treatment of lung cancer.

Metastatic associated proteins (MTA) are integrators of upstream regulatory signals with the ability to act as master coregulators for modifying gene transcriptional activity. The MTA family includes three genes and multiple alternatively spliced variants. The MTA proteins neither have their own enzymatic activity nor have been shown to directly interact with DNA. However, MTA proteins interact with a variety of chromatin remodeling factors and complexes with enzymatic activities for modulating the plasticity of nucleosomes, leading to the repression or derepression of target genes or other extra-nuclear and nucleosome remodeling and histone deacetylase (NuRD)-complex independent activities. The functions of MTA family members are driven by the steady state levels and subcellular localization of MTA proteins, the dynamic nature of modifying signals and enzymes, the structural features and post-translational modification of protein domains, interactions with binding proteins, and the nature of the engaged and resulting features of nucleosomes in the proximity of target genes. In general, MTA1 and MTA2 are the most upregulated genes in human cancer and correlate well with aggressive phenotypes, therapeutic resistance, poor prognosis and ultimately, unfavorable survival of cancer patients. Here we will discuss the structure, expression and functions of the MTA family of genes in the context of cancer cells. [ABSTRACT FROM AUTHOR]

Aims: Metastasis-associated gene 2 (MTA2) is reported to play an important role in tumor progression, but little is known about the role of MTA2 in nasopharyngeal carcinoma (NPC). The aim of the study was to explore the expression and function of MTA2 in NPC. Methods: Expression of MTA2 in NPC tissues and cell lines was detected by immunohistochemistry and Western blotting. Relationship between MTA2 expression and clinicopathological features was analyzed. Stable MTA2-overexpressing and MTA2-siliencing NPC cells were established by transfection with plasmids encoding MTA2 cDNA and lentivirus-mediated short hairpin RNA, respectively. Cell viability was determined by Cell Counting Kit-8 and colony formation assay. Cell migration ability was evaluated by wound healing and transwell invasion assay. The impact of MTA2 knockdown on growth and metastasis of CNE2 cells in vivo was determined by nude mouse xenograft models. Expression of several Akt pathway proteins was detected by Western blotting. Results: MTA2 was upregulated in NPC tissues and three NPC cell lines detected (CNE1, CNE2, and HNE1). MTA2 expression was related to clinical stage and lymph node metastasis of patients with NPC. MTA2 upregulation promoted proliferation and invasion of CNE1 cells, while MTA2 depletion had opposite effects on CNE2 cells. Moreover, MTA2 depletion suppressed growth and metastasis of CNE2 cells in vivo. MTA2 overexpression activated Akt and upregulated the expression of matrix metalloproteinase 7 and cyclin D1. Conclusion: We conclude that MTA2 acts as an oncogene in tumorigenesis of NPC. MTA2 may be a potential target for gene therapy in NPC. [ABSTRACT FROM AUTHOR]

Background: We have preliminarily reported MTA2 expression in gastric cancer and its biological functions by using knockdown cell models, while the molecular mechanisms of MTA2 in regulating malignant behaviors are still unclear. Methods: MTA2 overexpression models were established by transfection assay in gastric cancer cells BGC-823 and MKN28. Cell proliferation assay, colony formation in soft agar, wound-healing assay and transwell migration assay were performed with MTA2 overexpression and negative control (NC) cells. Subcutaneous xenografts and pulmonary metastasis models by BGC-823/MTA2 and BGC-823/NC cells were used to observe the capacity of growth and metastasis in vivo. Differential gene expression in MTA2 knockdown and overexpression cells was analyzed by microarrays. IL-11, which demonstrated as differential expression in microarray, was detected by real-time PCR, western blot, ELISA and immunohistochemistry staining. Recombinant human IL-11 (rhIL-11) was administrated in cell proliferation and colony formation as rescue assay. Results: The numbers of colonies in soft agar were significantly more in BGC-823/MTA2 and MKN28/MTA2 cells, comparing with those in their NC cells. Capabilities of cell proliferation, wound-healing and cell migration were not significantly changed in MTA2 overexpression cells. The sizes of subcutaneous xenografts and pulmonary metastases of BGC-832/MTA2 cells were significantly larger than those in BGC-823/NC group. Differential expression of IL-11 was identified by genome expression microarray both in MTA2 knockdown and overexpression cells. IL-11 expression was elevated in BGC-823/MTA2 cells, whereas reduced in SGC-7901/shMTA2 cells. Administration of rhIL-11 recovered colony formation capacity of SGC-7901/shMTA2 cells. Conclusions: MTA2 overexpression enhances colony formation and tumor growth of gastric cancer cells, but not plays important role in cancer cell migration and metastasis. IL-11 is one of the downstream effectors of MTA2 in regulating gastric cancer cells growth. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a leading cause of cancer-related death worldwide. Transcription factors (TFs) are essential gene expression regulators, and play critical roles in cancer development. However, the biological actions and prognostic value of TFs in GC remain unclear. In this study, we identified a risk model based on a 14-TF signature to predict recurrence-free survival in patients with GC. We further analyzed the ability of 14-TF to predict recurrence-free survival time in GC and found that a higher expression level of metastasis-associated protein 2 (MTA2) was associated with shorter overall survival and disease-free survival time in GC. Through in vitro and in vivo experiments, we demonstrated that MTA2 significantly promotes GC growth and metastasis. Furthermore, we identified MTA2 binding to the promoter of minichromosome maintenance deficient 5 (MCM5), thereby promoting GC progression. Overall, these findings strongly support the prognostic potential of the 14-TFs signature and suggest that targeting MTA2 may be a promising strategy to treat GC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Substantial evidence supports the hypothesis that enhancers are critical regulators of cell-type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of LIM domain-binding protein 1 (LDB1)/cofactor of LIM homeodomain protein 2/nuclear LIMinteractor, interactingwith the enhancer-binding protein achaete-scute complex homolog 1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells. LDB1-mediated enhancer:promoter looping appears to be required for both activation and repression of these target genes. Although LDB1-dependent activated genes are regulated at the level of transcriptional initiation, the LDB1-dependent repressed transcription units appear to be regulated primarily at the level of promoter pausing, with LDB1 regulating recruitment of metastasis-associated 1 family, member 2, a component of the nucleosome remodeling deacetylase complex, on these negative enhancers, required for the repressive enhancer function. These results indicate that LDB1-dependent looping events can deliver repressive cargo to cognate promoters to mediate promoter pausing events in a pituitary cell type. [ABSTRACT FROM AUTHOR]

Metastasis is the ultimate cause of death for most cancer patients. While many mechanisms have been delineated for regulation of growth and tumor initiation of the primary tumor, very little is known about the process of metastasis. Metastasis requires dynamic alteration of cellular processes in order for cells to disseminate from the primary tumor to distant sites. These alterations often involve dramatic changes in the regulation of cytoskeletal and cell-environment interactions. Furthermore, controlled refinement of these interactions requires feedback to regulatory networks in the nucleus. MTA2 is a member of the metastasis tumor-associated family of transcriptional regulators and is a central component of the nucleosome remodeling and histone deacetylation complex. MTA2 acts as a central hub for cytoskeletal organization and transcription and provides a link between nuclear and cytoskeletal organization. We will focus on MTA2 in this chapter, especially its role in breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Metastasis tumor-associated protein 2 (MTA2) is a member of the MTA family that is closely associated with tumor progression and metastasis. However, the role of MTA2 in glioma cells remains unclear. The expression of MTA2 was measured using immunohistochemistry and western blotting in the human brain tumor tissue array and human glioma cell lines. The impact of MTA2 knockdown on GBM8401 and Hs683 cell growth was evaluated by MTT assay and flow cytometry. Cell migration and invasion were analyzed by cell-migration assay and Matrigel invasion assay. In addition, we used subcutaneous tumor models to study the effect of MTA2 on the growth of glioma cells in vivo. We found that MTA2 protein and mRNA expression are higher in GBM8401 and Hs683 cells than in other glioma cells (M059 J, M059 K and U-87 MG), and glioma tumor tissue correlated significantly with tumor grade (P < 0.001). Knockdown of MTA2 expression significantly inhibited cell growth, cell migration and invasion, and induced G0/G1 phase arrest in human GBM8401 and Hs683 cells in vitro. Moreover, in vivo studies using subcutaneous xenografts in mice models indicate that MTA2 knockdown significantly inhibited tumorigenicity. These results indicate that MTA2 plays an important oncogenic role in the development and progression of gliomas. [ABSTRACT FROM AUTHOR]

Highlights: [•] MTA2 is acetylated at K152. [•] Histone acetyltransferase p300 binds to and acetylates MTA2. [•] Mutation of the MTA2 acetylation site inhibits the growth of colorectal cancer cells. [ABSTRACT FROM AUTHOR]

Metastasis remains a major clinical problem in breast cancer. One family of genes previously linked with metastasis is the metastasis tumor-associated (MTA) family, with members MTA1 enhancing and MTA3 inhibiting cancer metastasis. We have previously found that MTA2 enhances anchorage-independent growth in estrogen receptor α (ERα) breast cancers, and, in combination with other genes, performed as a predictive biomarker in ERα-positive breast cancer. We therefore hypothesized that MTA2 enhances breast cancer progression. To test this, cell growth, soft-agar colony formation, migration, and in vivo metastasis were examined in MTA2-overexpressing and Vector control transfected ERα-negative breast cancer cells. Pathways regulating cell-cell interaction, adhesion, and signaling through the Rho pathway were also investigated. Effects of the inhibition of the Rho pathway using a Rho Kinase inhibitor were assessed in soft-agar colony formation and motility assays in MTA2-overexpressing cells. MTA2 expression was associated with poor prognostic markers, and levels of MTA2 were associated with increased risk of early recurrence in retrospective analyses. MTA2 overexpression was associated with enhanced metastasis, and pathways regulating cell-cell interactions in vitro and in vivo. Most critically, MTA2-enhanced motility could be blocked by inhibiting Rho pathway signaling. We present the novel finding that MTA2 defined a subset of ERα-negative patients with a particularly poor outcome. [ABSTRACT FROM AUTHOR]

Background: MTA2 gene belongs to metastasis associated family, and is highly expressed in some solid tumors, including gastric cancer. Its biological function in gastric cancer is currently undefined. Methods: Metastasis-associated tumor gene family 2 (MTA2) and transcription factor specificity protein 1 (Sp1) expression were detected in 127 gastric cancer samples by immunohistochemistry staining. SGC-7901 and AGS gastric cancer cell lines transfected by MTA2 shRNA was used for biological function investigation. Binding and regulation activities of Sp1 on MTA2 promoter were investigated by chromatin immunoprecipitation and luciferase reporter gene. Results: The expression rate of MTA2 in gastric cancer tissues was 55.9% (71/127), and its expression was closely related to the depth of tumor invasion, lymph nodes metastasis, and TNM staging. MTA2 knockdown in human SGC-7901 and AGS gastric cancer cells significantly inhibited migration and invasion in vitro, and disrupted structure of cytoskeleton. MTA2 knockdown also attenuated xenografts growth and lung metastasis in nude mice model. MTA2 expression was positively correlated with transcription factor Sp1 in gastric cancer tissues (r = 0.326, P < 0.001). Sp1 bound to human MTA2 gene promoter at region from -1043 bp to -843 bp. Transcriptional activity of MTA2 promoter could be enhanced by Sp1 overexpression. Conclusions: MTA2 knockdown impairs invasion and metastasis of gastric cancer cells, and attenuates xenografts growth in vivo. Sp1 regulates MTA2 expression at transcriptional level. [ABSTRACT FROM AUTHOR]

The aim of this study was to detect MTA2 expression in pancreatic ductal adenocarcinoma (PDA) and to analyze its association with prognosis of PDA patients. MTA2 mRNA and protein expression were determined by real-time quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry in specimens of primary cancer and their adjacent noncancerous tissues in PDA patients. We found that MTA2 mRNA and protein expression levels were both significantly upregulated in PDA lesions compared with adjacent noncancerous tissues. Immunohistochemistry showed that high MTA2 expression was correlated with poor tumor differentiation, TNM stage, and lymph node metastasis. Kaplan-Meier survival analysis showed that patients with high expression levels of MTA2 showed lower overall survival rate than those with low expression levels. Multivariate analysis showed that high MTA2 protein expression was an independent prognostic factor for PDA patients. Our study suggests that overexpression of MTA2 may play an important role in the progression of PDA and MTA2 expression may serve as a biomarker for poor prognosis for PDA. [ABSTRACT FROM AUTHOR]

Thymomas of the same histological subtype sometimes manifest different biological behaviors. Metastasis Tumor Antigen-2 (MTA2) is targeted by the transcriptional repressor Kaiso, the distribution which is thought to be modulated by p120catenin (p120ctn). It is currently unclear if expression of p120ctn, Kaiso, and MTA2 relates to the biological behavior of thymoma. P120ctn, Kaiso, and MTA2 expression were examined in 137 cases of thymoma, three cases of thymic carcinoma, and 18 paired autologous normal thymic tissues using immunohistochemistry, and correlation of these proteins with histological subtypes and clinical stages were analyzed. In normal thymic epithelial cells, p120ctn was expressed on the cell membrane but Kaiso and MTA2 were not detected. Membranous p120ctn expression was reduced in thymoma epithelial cells, while ectopic cytoplasmic expression was observed in 76.6 % (105/137) of the cases. Cytoplasmic Kaiso was detected in 69.3 % (95/137) and nuclear MTA2 was detected in 70.8 % (97/137) of the thymomas. There were good consistencies (Kappa = 0.559, 0.512, 0.652; all P < 0.001) and correlations ( r = 0.733, 0.652, 0.708; all P < 0.001) between cytoplasmic p120ctn, cytoplasmic Kaiso, and nuclear MTA2 expression in thymomas. All three protein factors correlated with histological type and clinical stage in thymoma ( P < 0.05). Specifically, cytoplasmic p120ctn and Kaiso expression and nuclear MTA2 expression were higher in high-risk (types B2 and B3) thymomas and Masaoka stage III/IV thymomas than low-risk (types A, AB, and B1) and stage I/II thymomas (both P < 0.001), respectively. Cytoplasmic p120ctn, cytoplasmic Kaiso, and nuclear MTA2 expression correlated directly with histological type and Masaoka stage and may thus be used as potential biomarkers to predict biological behavior of thymoma. [ABSTRACT FROM AUTHOR]

[Display omitted] • Numerous genes that contribute to the antiviral state remain to be identified. • A screen recovered host proteins that modulate ZIKV replication in IFN-stimulated cells. • APOL3 acts as a proviral factor for ZIKV and several other RNA viruses. • MTA2 is as a potent flavivirus-specific antiviral gene. • Our study opens perspectives to target weakness points in the life cycle of viruses. Establishment of the interferon (IFN)-mediated antiviral state provides a crucial initial line of defense against viral infection. Numerous genes that contribute to this antiviral state remain to be identified. Using a loss-of-function strategy, we screened an original library of 1156 siRNAs targeting 386 individual curated human genes in stimulated microglial cells infected with Zika virus (ZIKV), an emerging RNA virus that belongs to the flavivirus genus. The screen recovered twenty-one potential host proteins that modulate ZIKV replication in an IFN-dependent manner, including the previously known IFITM3 and LY6E. Further characterization contributed to delineate the spectrum of action of these genes towards other pathogenic RNA viruses, including Hepatitis C virus and SARS-CoV-2. Our data revealed that APOL3 acts as a proviral factor for ZIKV and several other related and unrelated RNA viruses. In addition, we showed that MTA2, a chromatin remodeling factor, possesses potent flavivirus-specific antiviral functions induced by IFN. Our work identified previously unrecognized genes that modulate the replication of RNA viruses in an IFN-dependent manner, opening new perspectives to target weakness points in the life cycle of these viruses. [ABSTRACT FROM AUTHOR]

In order to investigate the roles of MTA2 in the pathogenesis of ovarian epithelial cancer, the expression of MTA2 in 4 ovarian cell lines were detected by semi-quantitative RT-PCR and Western-blot assays. MTA2 expression in normal, borderline, benign and malignant epithelial ovarian tissues was immunohistochemically examined. The expression of MTA2 mRNA and protein was detected in all of 4 cell lines of ovarian epithelial cancer. The expression of MTA2 mRNA and protein was higher in strong migration cell lines than in weak migration ones. In borderline and malignant ovarian tissues tested, MTA2 staining was dramatically stronger than in normal and benign tissues ( P<0.01). The expression levels in malignant ovarian tissues were significantly higher than that in borderline epithelial ovarian tissues ( P<0.01). The expression of MTA2 was correlated with clinical stage, histopathological grade and lymph node metastasis. It was concluded that the high expression of MTA2 was associated with more aggressive behaviors of epithelial ovarian cancer. MTA2 provides a novel indicator of ovarian cancer. [ABSTRACT FROM AUTHOR]