The HDAC2-MTA3 interaction induces nonsmall cell lung cancer cell migration and invasion by targeting c-Myc and cyclin D1.

Genome-wide association studies have identified numerous single-nucleotide polymorphisms (SNPs) associated with lung cancer; however, the functions of histone deacetylase 2 (HDAC2) rs13213007 and HDAC2 in nonsmall cell lung cancer (NSCLC) remain unclear. Here we identified HDAC2 rs13213007 as a risk SNP and showed that HDAC2 was upregulated in both peripheral blood mononuclear cells (PBMCs) and NSCLC tissues with the rs13213007 A/A genotype compared with those with the rs13213007 G/G or G/A genotype. Patient clinical data indicated strong associations between rs13213007 genotype and N classification. Immunohistochemical staining confirmed that higher expression of HDAC2 was associated with NSCLC progression. Furthermore, we generated 293T cells with the rs13213007 A/A genotype using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing. Chromatin immunoprecipitation sequencing followed by motif analysis showed that HDAC2 can bind to c-Myc in rs13213007 A/A 293T cells. Cell Counting Kit-8, colony formation, wound-healing, and Transwell assays revealed that HDAC2 upregulates c-Myc and cyclin D1 expression and promotes NSCLC cell proliferation, migration, and invasion. Co-immunoprecipitation, quantitative reverse transcription-polymerase chain reaction, and western blot analysis assays showed that MTA3 interacts with HDAC2, decreases HDAC2 expression, and rescues the migration and invasion abilities of NSCLC cells. Taken together, these findings identify HDAC2 as a potential therapeutic biomarker in NSCLC.

Long non-coding RNA HCG11 suppresses the growth of glioma by cooperating with the miR-4425/MTA3 axis.

BACKGROUND: Glioma is a type of malignant tumor that occurs in the central nervous system of adults. Long non-coding RNAs (lncRNAs) that potentially participate in the initiation and progression of glioma have been widely reported. As a now-found lncRNA, HLA complex group 11 (HCG11) has not yet been studied in glioma. The present study aimed to determine the role of HCG11 in the tumorigenesis of glioma. METHODS: A quantitative real-time polymerase chain reaction assay was performed to examine the expression pattern of HCG11 in 84 glioma tissues and cell lines. The overall survival rate of glioma patients with a high or low level of HCG11 or metastasis-associated 1 family member 3 (MTA3) was analyzed by Kaplan-Meier analysis. The effect of HCG11 on glioma cell growth was determined by in vitro and in vivo experiments. MicroRNAs (miRNAs) that potentially interact with HCG11 were searched and determined by bioinformatics analysis and a luciferase reporter assay. Similarly, the target of miRNA-4425 was identified. Finally, rescue assays were conducted to determine the bio-function of the competing endogenous RNA pathway. RESULTS: HCG11 was downregulated in 84 pairs of glioma tissues and cell lines. Moreover, a low level of HCG11 indicted the lower overall survival rate of glioma patients. Regarding the mechanism, HCG11 was abundant in the cytoplasm of glioma cells and interacted with miR-4425 to release the expression of MTA3. miR-4425 and MTA3 participated in HCG11-mediated glioma growth. CONCLUSIONS: LncRNA HCG11 suppresses the growth of glioma by cooperating with the miR-4425/MTA3 axis.

Catalpol inhibits cell proliferation, invasion and migration through regulating miR-22-3p/MTA3 signalling in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver malignancy with high rates of recurrence and mortality worldwide. Unfortunately, effective strategies for the management of HCC are still unsatisfactory. The aim of this investigation is to explore the effects of catalpol on HCC progression and investigated the mechanistic functions of catalpol in HCC. Catalpol significantly suppressed cell viability, caused the suppression in colony growth, decreased number of invaded and migrated HCC cells, and increased the rates of apoptotic cells and proportions of HCC cells at G0/G1 cell cycle phase. Furthermore, catalpol dramatically up-regulated miR-22-3p expression in HCC cells, and knockdown of miR-22-3p attenuated the anti-tumor effects of catalpol in HCC. Additionally, results from luciferase reporter assay demonstrated that miR-22-3p targeted the metastasis associated 1 family member 3 (MTA3) 3'untranslated region (3'UTR), and miR-22-3p down-regulated MTA3 expression in HCC cells. Overexpression of MTA3 enhanced HCC cell proliferative abilities, increased the number of invasive and migratory HCC cells, and also attenuated the anti-tumor potentials of catalpol in HCC. Catalpol suppressed HCC tumor growth and increased miR-22-3p expression, while down-regulated MTA3 expression in dissected tumor tissues from xenograft nude mice. Collectively, our results for the first time revealed the anti-tumor potentials of catalpol in HCC, and the anti-tumor effects mediated by catalpol were via modulating the miR-22-3p/MTA3 axis in HCC.

Bisphenol A-elicited miR-146a-5p impairs murine testicular steroidogenesis through negative regulation of Mta3 signaling.

The epigenetic effects on expression of non-coding RNAs (e.g. microRNAs) of environmental toxin bisphenol A (BPA) have extended our understanding of the etiology of human reproductive disorders including hypospermatogenesis and androgen deficiency. BPA-induced miR-146a-5p is a potent regulator of endocrine and immune homeostasis, but its role in testis remain unexplored. We show here that in murine testis, miR-146a-5p was exclusively expressed in interstitial Leydig cells (LCs). This expression was significantly induced by BPA exposure. Consequently, the elevated miR-146a-5p exacerbated the deleterious effects of BPA on testicular steroidogenesis. Mechanistically, miR-146a-5p repressed the expression of Mta3, a pivotal chromatin remodeling transcription factor recently involved in controlling the steroidogenic activity, via directly targeting its 3'UTR. This repression thereafter rendered LCs more sensitive to BPA-elicited inhibitory effects. Conversely, ectopic expression of hMTA3 successfully rescued miR-146a-5p-elicited inhibitory effects on testicular steroidogenesis in BPA-challenged LCs. Taken together, the available data provide novel evidence that deregulation of testicular miR-146a-5p/Mta3 cascade mediates, at least in part, the steroidogenic dysfunction caused by BPA exposure.

MTA3 regulates malignant progression of colorectal cancer through Wnt signaling pathway.

MTA3 overexpression has been implicated in carcinogenesis. The aim of the present study was to explore the clinical significance and biological roles of MTA3 in human colorectal cancer and colorectal cancer cells. A total of 80 cases of colorectal cancer tissues were examined by immunohistochemistry for MTA3 protein expression. We analyzed the relationship between MTA3 and clinical factors and the results showed that MTA3 was overexpressed in 51.25% (41/80) cancer cases. There was significant associations between MTA3 overexpression and advanced TNM stage (p = 0.0086) and Ki67 index (p = 0.001). We overexpressed MTA3 in LoVo cells and depleted its expression in HCT15 cells. The results showed that MTA3 promoted cancer cell proliferation, invasion, migration, and cell cycle progression, and inhibited 5-fluorouracil-induced apoptosis in LoVo cell line. MTA3 depletion in HCT15 cell line showed the opposite effects. In addition, we found that MTA3 positively regulated cell cycle proteins including cyclin D1 and cyclin E. It also upregulated Bcl2 and downregulated Bax expression. Furthermore, we found that MTA3 could activate Wnt signaling pathway by upregulating Wnt target proteins. Our results demonstrated that MTA3 overexpression contributes to colorectal cancer carcinogenesis, progression, and chemoresistance. MTA3 could serve as a potential therapeutic target in colorectal cancer.

Overexpression of the metastasis-associated gene MTA3 correlates with tumor progression and poor prognosis in hepatocellular carcinoma.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers in the world. However, there remains a lack of effective diagnostic and treatment markers. We aimed to explore metastasis-associated protein 3 (MTA3) expression and function in HCC and its relationship with clinicopathological factors. METHODS: We investigated the expression pattern and clinicopathological significance of MTA3 in 90 patients with HCC via immunohistochemistry and explored MTA3 function via gene knockdown of MTA3. RESULTS: MTA3 was overexpressed in HCC cell nuclei and downregulated in HCC cell cytoplasm. The former finding correlated with metastasis (P = 0.010) and poor prognosis (P = 0.018). In addition, deleting MTA3 inhibited HCC cell growth, invasion, and metastasis in vitro, as shown in the colony formation, migration, and wound-healing assays. CONCLUSIONS: These results indicate that MTA3 is an oncogene of HCC, predicts poor prognosis of HCC, and may be a future marker of HCC treatment.

Expression of metastasis-associated protein 3 in human brain glioma related to tumor prognosis.

Glioma represents a disparate group of tumors characterized by high invasion ability, and therefore it is of clinical significance to identify molecular markers and therapeutic targets for better clinical management. Previously, metastasis-associated protein family (MTA) is considered to promote tumor cell invasion and metastasis of human malignancies. Recently, the newly identified MTA3 has been shown to play conflicting roles in human malignancies, while the expression pattern and potential clinical significance of MTA3 in human glioma have not been addressed yet. In the present study, we investigated the protein expression of MTA3 by immunohistochemistry assay and analyzed its association with glioma prognosis in 186 cases of patients. Results showed that MTA3 expression was decreased in glioma compared with that in normal brain (P < 0.05). In addition, tumors with high MTA3 expression were more likely to be of low WHO grade (P = 0.005) and reserve of body function (P = 0.014). Survival analysis showed that decreased MTA3 expression was independently associated with unfavorable overall survival of patients (P < 0.001). These results provide the first evidence that MTA3 expression was decreased in human glioma and negatively associated with prognosis of patients, suggesting that MTA3 may play a tumor suppressor role in glioma.

Snail/beta-catenin signaling protects breast cancer cells from hypoxia attack.

The tolerance of cancer cells to hypoxia depends on the combination of different factors--from increase of glycolysis (Warburg Effect) to activation of intracellular growth/apoptotic pathways. Less is known about the influence of epithelial-mesenchymal transition (EMT) and EMT-associated pathways on the cell sensitivity to hypoxia. The aim of this study was to explore the role of Snail signaling, one of the key EMT pathways, in the mediating of hypoxia response and regulation of cell sensitivity to hypoxia, using as a model in vitro cultured breast cancer cells. Earlier we have shown that estrogen-independent HBL-100 breast cancer cells differ from estrogen-dependent MCF-7 cells with increased expression of Snail1, and demonstrated Snail1 involvement into formation of hormone-resistant phenotype. Because Snail1 belongs to hypoxia-activated proteins, here we studied the influence of Snail1 signaling on the cell tolerance to hypoxia. We found that Snail1-enriched HBL-100 cells were less sensitive to hypoxia-induced growth suppression if compared with MCF-7 line (31% MCF-7 vs. 71% HBL-100 cell viability after 1% O2 atmosphere for 3 days). Snail1 knock-down enhanced the hypoxia-induced inhibition of cell proliferation giving the direct evidence of Snail1 involvement into cell protection from hypoxia attack. The protective effect of Snail1 was shown to be mediated, at least in a part, via beta-catenin which positively regulated expression of HIF-1-dependent genes. Finally, we found that cell tolerance to hypoxia was accompanied with the failure in the phosphorylation of AMPK - the key energy sensor, and demonstrated an inverse relationship between AMPK and Snail/beta-catenin signaling. Totally, our data show that Snail1 and beta-catenin, besides association with loss of hormone dependence, protect cancer cells from hypoxia and may serve as an important target in the treatment of breast cancer. Moreover, we suggest that the level of these proteins as well the level of AMPK phosphorylation may be considered as predictors of the tumor sensitivity to anti-angiogenic drugs.

Prognostic and immunological significance of metastasis-associated protein 3 in patients with thymic epithelial tumors.

BACKGROUND: Immune checkpoint inhibitors have shown promising anticancer activity and have recently been proposed as a therapy for thymic epithelial tumors (TETs); however, this treatment is only effective for a subgroup of TET patients. Thus, this study aims to identify the potential genes implicated in the regulation of cancer immunity in TETs. METHODS: The TETs RNA-seq and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. The clinical significance of the tumor microenvironment (TME) in TETs was evaluated. Weighted gene coexpression network analysis (WGCNA) was used to identify the immune response-related hub genes. The expression of metastasis-associated protein 3 (MTA3) in TETs was investigated in public datasets and a patient cohort. Kaplan‒Meier curves were generated to analyze the prognostic value of various factors. The Tumor Immune Estimation Resource (TIMER2.0) was used to estimate the relevance of MTA3 to immune cell infiltration. Gene set enrichment analysis (GSEA) and pathway enrichment analysis were applied to explore the MTA3-related pathways. RESULTS: The TME was found to be clinically significant in TETs. Moreover, MTA3 was identified as a key gene associated with the immune score, and lower MTA3 expression was linked to poor TME and reduced cytotoxic activity in TETs. Furthermore, MTA3 was found to be deregulated in TETs, predictive of poor prognosis. MTA3 was also significantly associated with the infiltration levels of various immune cell types and highly correlated with their corresponding markers. Notably, MTA3 was positively associated with various immune response pathways. CONCLUSION: MTA3 is clinically significant in TETs and correlated with immune cell infiltration. Thus, MTA3 might be a biomarker for predicting the prognosis and immune status of TET patients.

[Corrigendum] High glucose promotes hepatic fibrosis via miR­32/MTA3­mediated epithelial­to­mesenchymal transition.

Subsequently to the publication of this paper, the authors have realized that Fig. 2 was published containing some incorrectly assembled data panels. The E­cadherin control data panel in Fig. 3F was re­used in Fig. 2C; furthermore, the HG / Vimentin data panel in Fig. 4E was re­used in Fig. 2D. The authors have re­examined their original data, and were able to identify that Fig. 2 contained the erroneously assembled data panels. The revised version of Fig. 2, showing the correct E­cadherin control data panel for Fig. 2C and the correct HG / Vimentin data panel for Fig. 2D, is shown below. It was also noted that the white rectangles were not explained in the figure legend; these represent an enlargement of the cells in the E­cad/vimentin panels, and the details are now included in the figure legend (shown in bold). Note that these errors did not significantly affect either the results or the conclusions reported in this paper, and all the authors agree to the publication of this corrigendum. Furthermore, the authors thank the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 19: 3190­3200, 2019; DOI: 10.3892/mmr.2019.9986].

Layilin enhances the invasive ability of malignant glioma cells via SNAI1 signaling.

BACKGROUND: Malignant gliomas are characterized by high invasive ability. In this study, we investigated roles of layilin, a C-type lectin-homologous protein, in the invasive ability of malignant glioma cells. METHODS: Expression of layilin was investigated by western blotting in the malignant glioma cell lines of U251-MG, A172, and T98G and in astrocytes. The effects of layilin-knockdown on the expression and protein levels of snail family transcriptional repressor 1 (SNAI1), a transcriptional factor involved in the acquisition and enhancement of invasive ability in malignant gliomas, and on the expression of its target genes, matrix metalloproteinase 2 (MMP2), MMP9, and collagen type I alpha 1 chain (COL1A1), were investigated by qPCR and/or western blotting. Furthermore, the effects of layilin-knockdown on the expression and protein levels of metastasis associated 1 family member 3 (MTA3), a transcriptional repressor of SNAI1, were also investigated by qPCR and western blotting. Finally, the effects of layilin-knockdown on the invasive ability of the cells were investigated by a wound healing assay. RESULTS: All the tested malignant glioma cells highly expressed layilin, compared to astrocytes, one of representative glial cell types. Layilin-knockdown reduced SNAI1 both at the mRNA and protein levels in A172 cells, and consequently mRNA levels of MMP2, MMP9, and COL1A1 were also reduced. Furthermore, layilin-knockdown increased nuclear protein levels of MTA3 in A172 cells. Notably, layilin-knockdown suppressed the invasive ability of the cells. CONCLUSION: Layilin up-regulates the expression of SNAI1 via down-regulation of MTA3. This process enhances the invasive ability of malignant glioma cells.

Emodin alleviates cardiac fibrosis by suppressing activation of cardiac fibroblasts via upregulating metastasis associated protein 3.

Excess activation of cardiac fibroblasts inevitably induces cardiac fibrosis. Emodin has been used as a natural medicine against several chronic diseases. The objective of this study is to determine the effects of emodin on cardiac fibrosis and the underlying molecular mechanisms. Intragastric administration of emodin markedly decreased left ventricular wall thickness in a mouse model of pathological cardiac hypertrophy with excess fibrosis induced by transaortic constriction (TAC) and suppressed activation of cardiac fibroblasts induced by angiotensin II (AngII). Emodin upregulated expression of metastasis associated protein 3 (MTA3) and restored the MTA3 expression in the setting of cardiac fibrosis. Moreover, overexpression of MTA3 promoted cardiac fibrosis; in contrast, silence of MTA3 abrogated the inhibitory effect of emodin on fibroblast activation. Our findings unraveled the potential of emodin to alleviate cardiac fibrosis via upregulating MTA3 and highlight the regulatory role of MTA3 in the development of cardiac fibrosis.

MTA3-SOX2 Module Regulates Cancer Stemness and Contributes to Clinical Outcomes of Tongue Carcinoma.

Cancer cell plasticity plays critical roles in both tumorigenesis and tumor progression. Metastasis-associated protein 3 (MTA3), a component of the nucleosome remodeling and histone deacetylase (NuRD) complex and multi-effect coregulator, can serve as a tumor suppressor in many cancer types. However, the role of MTA3 in tongue squamous cell cancer (TSCC) remains unclear although it is the most prevalent head and neck cancer and often with poor prognosis. By analyzing both published datasets and clinical specimens, we found that the level of MTA3 was lower in TSCC compared to normal tongue tissues. Data from gene set enrichment analysis (GSEA) also indicated that MTA3 was inversely correlated with cancer stemness. In addition, the levels of MTA3 in both samples from TSCC patients and TSCC cell lines were negatively correlated with SOX2, a key regulator of the plasticity of cancer stem cells (CSCs). We also found that SOX2 played an indispensable role in MTA3-mediated CSC repression. Using the mouse model mimicking human TSCC we demonstrated that the levels of MTA3 and SOX2 decreased and increased, respectively, during the process of tumorigenesis and progression. Finally, we showed that the patients in the MTA3low/SOX2high group had the worst prognosis suggesting that MTA3low/SOX2high can serve as an independent prognostic factor for TSCC patients. Altogether, our data suggest that MTA3 is capable of repressing TSCC CSC properties and tumor growth through downregulating SOX2 and MTA3low/SOX2high might be a potential prognostic factor for TSCC patients.

The Homeotic Protein SIX3 Suppresses Carcinogenesis and Metastasis through Recruiting the LSD1/NuRD(MTA3) Complex.

The homeodomain transcription factor SIX3 was recently reported to be a negative regulator of the Wnt pathway and has an emerging role in cancer. However, how SIX3 contributes to tumorigenesis and metastasis is poorly understood. METHODS: We employed affinity purification and mass spectrometry (MS) to identify the proteins physically associated with SIX3. Genome-wide analysis of the SIX3/LSD1/NuRD(MTA3) complex using a chromatin immunoprecipitation-on-chip approach identified a cohort of target genes including WNT1 and FOXC2, which are critically involved in cell proliferation and epithelial-to-mesenchymal transition. Also, we used flow cytometry, growth curve analysis, EdU incorporation assay, colony formation assays, trans-well invasion assays, immunohistochemical staining and in vivo bioluminescence assay to investigate the function of SIX3 in tumorigenesis. RESULTS: We demonstrate that the SIX3/LSD1/NuRD(MTA3) complex inhibits carcinogenesis in breast cancer cells and suppresses metastasis in breast cancer. SIX3 expression is downregulated in various human cancers and high SIX3 is correlated with improved prognosis. CONCLUSION: Our study revealed an important mechanistic link between the loss of function of SIX3 and tumor progression, identified a molecular basis for the opposing actions of MTA1 and MTA3, and may provide new potential prognostic indicators and targets for cancer therapy.

Metastasis-associated protein 3 in colorectal cancer determines tumor recurrence and prognosis.

Metastasis-associated protein family (MTA) promotes tumor cell invasion and metastasis of human malignancies. However, the novel component of MTA family, MTA3 was found to play conflicting roles in human malignancies. While the expression pattern and potential function of MTA3 in colorectal cancer has not been addressed yet. In the present study, we investigated the protein expression of MTA3 by immunohistochemistry assay, analyzed its association with tumor progression, recurrence and prognosis in239 cases of patients. Results showed that MTA3 expression in colorectal cancer was significantly decreased in colorectal cancer compared with normal specimens. Its expression was found to be correlated with tumor differentiation, metastases and TNM stage. Kaplan-Meier analysis proved that MTA3 was associated with both disease-free survival and overall survival of patients with colorectal cancer that patients with negative MTA3 expression tend to have unfavorable outcome. Moreover, cox's proportional hazards analysis showed that negative MTA3 expression was an independent prognostic marker of poor outcome. These results provided the first evidence that MTA3 level was decreased in colorectal cancer and significantly correlated with tumor cell invasion and metastasis. It also demonstrated that MTA3 might serve as a potential marker of tumor recurrence and prognosis of colorectal cancer.

MiR-367 regulates cell proliferation and metastasis by targeting metastasis-associated protein 3 (MTA3) in clear-cell renal cell carcinoma.

Clear-cell renal cell carcinoma (ccRCC) is an aggressive and malignant kidney cancer which has the worst prognosis. Although microRNAs (miRNAs) have recently been identified as a novel class of regulators in oncogenesis and metastasis, there are few studies on their participation in ccRCC. In the present study, we observed that miR-367 expression was increased in both human ccRCC tissues and cell lines. Cell proliferation was evaluated by MTT assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay kit, which indicated that inhibition of miR-367 could suppress the ccRCC proliferation. Forced expression of miR-367 substantially induced cell migration and invasion evidenced by wound-healing and transwell assays, and this carcinogenesis could be abolished by miR-367 inhibitor treatment. Further analysis identified Metastasis-Associated Protein 3 (MTA3) as a direct target of miR-367. QRT-PCR and western blot results indicated the correlative expression of miR-367 and MTA3 in ccRCC tissue samples. Overexpression of MTA3 reversed miR-367-induced cell proliferation, migration and invasion. Our data uncovered a novel molecular interaction between miR-367 and MTA3, indicating a therapeutic strategy of miR-367 for ccRCC.

MTA3 Regulates Extravillous Trophoblast Invasion Through NuRD Complex.

Extravillous trophoblast (EVT) invasion is required for remodeling uterine tertiary arteries and placenta development during pregnancy. Compromised EVT invasion may contribute to the pathology of placenta-related diseases. Metastasis -associated protein 3 (MTA3) is one of the subunits of nucleosome remodeling and deacetylation (NuRD) complex that represses transcription in a histone deacetylase-dependent manner. MTA3 is reported to be down-regulated in preeclamptic placentas, suggesting its potential role in EVT invasion. Here, we investigate the role of MTA3 in EVT invasion by studying its molecular mechanisms in EVT cells. First, we confirmed MTA3 expression in the EVT cells in human placenta using immunohistochemistry. We then used lentivirus-mediated MTA3 short hairpin RNA (shRNA) to knock down MTA3 expression in EVT-derived HTR8/SVneo cells and found higher invasion capacity in MTA3 knockdown cells. Using quantitative real-time PCR, we showed higher expression of invasion-related genes matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and transcription factor Snail in MTA3 knockdown compared with control cells. Co-immunoprecipitation-Western blot assay showed the protein-protein interaction of histone deacetylase 1 (HDAC1), a subunit of NuRD, with MTA3 in HTR8/SVneo cells. Co-immunoprecipitation-Mass spectrometry assay further identified 71 proteins interacting with MTA3, including NuRD subunits, heterochromatin proteins, epigenetics modifiers and transcription factors. This result not only indicated the involvement of NuRD complex in MTA3's function, but also demonstrated the complicated multiple co-players in MTA3 and NuRD complex mediated transcription repression in EVT. In summary, our data demonstrates that MTA3 regulates EVT invasion and related gene expression via NuRD complex in EVT.

Structure, expression and functions of MTA genes.

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.

MTA3 regulates differentiation of human cytotrophoblast stem cells.

INTRODUCTION: Early placental development depends on the correct balance of cytotrophoblast (CTB) proliferation and differentiation, into either syncytiotrophoblast (STB) involved in nutrient/gas exchange, or invasive extravillous trophoblast (EVT) involved in establishment of blood flow to the placenta. Metastasis associated protein-3 (MTA3) is a transcriptional co-repressor known to regulate cell migration. In addition, MTA3 is reportedly decreased in preeclampsia. We set out to investigate the role of MTA3 in human trophoblast differentiation. METHODS: We co-stained first and third trimester placental sections with antibodies to MTA3 and other trophoblast markers. We also evaluated MTA3 expression following in vitro differentiation of primary isolated CTB. In order to evaluate the role of MTA3 in trophoblast differentiation, we used lentiviral constructs to overexpress and knock down its expression. Trophoblast differentiation was assessed by a combination of marker expression and functional assays, including hCG ELISA and cell migration. RESULTS: MTA3 was abundantly expressed in CTB and proximal cell column EVT in the human placenta and decreased with further differentiation into STB and mature EVT. MTA3 knockdown in JEG3 resulted in a 2-3 fold decrease in STB markers, CGB and GCM1, as well as in hCG secretion. In terms of EVT differentiation, MTA3 knockdown led to a 1.5-2 fold increase in HLA-G and cell migration, but decreased the mature EVT marker ITGA1. DISCUSSION: Taken together, our data suggest a role for MTA3 in terminal trophoblast differentiation into both hCG-secreting STB and mature EVT.