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Background/aim: Metastasis-associated gene 1 (MTA1) is considered a potential prognostic factor in esophageal cancer. We investigated the clinical relationship between MTA1, LAT1, and tumor metabolism, as evaluated by positron emission tomography (PET) in esophageal squamous cell carcinoma., Materials and Methods: We analyzed 142 esophageal squamous cell carcinoma patients who underwent curative resection without preoperative treatment. MTA1 expression was assessed by immuno-zahistochemistry, and tested against standardized uptake values from preoperative PET-CT. The association among MTA1, LAT1, and 18 FAMT PET results were analyzed., Results: MTA1 staining was observed in 82 of 142 cancer tissues. Five-year overall survival was 69.9 % in the absence of MTA1, but 50.7% otherwise (p=0.021), while disease-free survival was 66.5% and 49.0% (p=0.071), respectively. Abnormal 18 FAMT accumulation was noted in 13 patients without MTA1 and in 18 patients with MTA1 (p=0.079), with maximum standardized uptake value 1.6±1.6 and 2.7±1.6, respectively (p=0.036). MTA1 expression was positively correlated with LAT1 (p=0.013) and CD34 (p=0.034) expression, but not with Ki-67 (p=0.078)., Conclusion: MTA1 shows promise as a diagnostic and prognostic marker in esophageal cancer, and we anticipate that the gene will also prove to be a good therapeutic target., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The present study assessed the role of metastasis-associated protein 1 (MTA1) in epithelial to mesenchymal transition (EMT) and metastasis in non-small-cell lung cancer (NSCLC) cells using a normal lung epithelium cell line, three NSCLC cell lines, a mouse NSCLC model, and 56 clinical NSCLC samples. We observed that MTA1 overexpression decreased cellular adhesion, promoted migration and invasion, and changed cytoskeletal polarity. MTA1 knockdown had the opposite effects. MTA1 overexpression decreased E-cadherin, Claudin-1, and ZO-1 levels and increased Vimentin expression in vitro and in vivo, through activation of AKT/GSK3β/β-catenin signaling. However, treatment with the AKT inhibitor MK2206 did not completely rescue effects associated with MTA1 expression changes, indicating that pathways other than the AKT/GSK3β/β-catenin pathway could be involved in MTA1-induced EMT. Compared with normal lung tissues, MTA1 expression was elevated in NSCLC patient tissues and was correlated with American Joint Committee on Cancer stage, T stage, lymphatic metastasis, and patient overall survival. Additionally, MTA1 expression was positively associated with p-AKT and cytoplasmic β-catenin levels. These findings indicate MTA1 promotes NSCLC cell EMT and metastasis via AKT/GSK3β/β-catenin signaling, which suggests MTA1 may be an effective anti-NSCLC therapeutic target.

Emerging evidence indicates epigenetic modification represses estrogen receptor α (ERα) and contributes to the resistance to tamoxifen in aggressive ERα-negative (ERα-) breast cancer. Z-ligustilide is a major compound in Radix Angelica sinensis, an herb from traditional Chinese medicine (TCM) most frequently prescribed for breast cancer. However, the role of Z-ligustilide in ERα- breast cancer and epigenetic modification remains largely unknown. Herein we showed, for the first time, that Z-ligustilide restored the growth inhibition of tamoxifen on ERα- breast cancer cells. Apoptosis and S and G2/M phases cell cycle arrest were induced by combinatorial Z-ligustilide and tamoxifen. Importantly, Z-ligustilide reactivated the ERα expression and transcriptional activity, which is proved to be indispensable for restoring the sensitivity to tamoxifen. Interestingly, Z-ligustilide increased Ace-H3 (lys9/14) enrichment in the ERα promoter. Moreover, Z-ligustilide dramatically reduced the enrichment of metastasis-associated protein 1 (MTA1) as well as IFN-γ-inducible protein 16 (IFI16) and histone deacetylases (HDACs) onto the ERα promoter. Meanwhile, Z-ligustilide downregulated MTA1, IFI16 and HDACs, which caused destabilization of the corepressor complex. Collectively, our study not only highlights Z-ligustilide as a novel epigenetic modulator, but also opens new possibilities from TCM for treating aggressive tamoxifen-resistant breast cancer.

The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16-hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1. Furthermore, HIC1 SUMOylation is dispensable for DNA repair since the non-SUMOylatable E316A mutant is as efficient as wt HIC1 in Comet assays. Upon induction of irreparable DSBs, the ATM-mediated increase of HIC1 SUMOylation is independent of its effector kinase Chk2. Moreover, irreparable DSBs strongly increase both the interaction of HIC1 with MTA1 and MTA3 and their binding to the SIRT1 promoter. To characterize the molecular mechanisms sustained by this increased repression potential, we established global expression profiles of BJ-hTERT fibroblasts transfected with HIC1-siRNA or control siRNA and treated or not with etoposide. We identified 475 genes potentially repressed by HIC1 with cell death and cell cycle as the main cellular functions identified by pathway analysis. Among them, CXCL12, EPHA4, TGFβR3 and TRIB2, also known as MTA1 target-genes, were validated by qRT-PCR analyses. Thus, our data demonstrate that HIC1 SUMOylation is important for the transcriptional response to non-repairable DSBs but dispensable for DNA repair.

The nucleosome remodeling and deacetylase (NuRD) complex remodels the genome in the context of both gene transcription and DNA damage repair. It is essential for normal development and is distributed across multiple tissues in organisms ranging from mammals to nematode worms. In common with other chromatin-remodeling complexes, however, its molecular mechanism of action is not well understood and only limited structural information is available to show how the complex is assembled. As a step towards understanding the structure of the NuRD complex, we have characterized the interaction between two subunits: the metastasis associated protein MTA1 and the histone-binding protein RBBP4. We show that MTA1 can bind to two molecules of RBBP4 and present negative stain electron microscopy and chemical crosslinking data that allow us to build a low-resolution model of an MTA1-(RBBP4)2 subcomplex. These data build on our understanding of NuRD complex structure and move us closer towards an understanding of the biochemical basis for the activity of this complex., (© 2016 The Protein Society.)

The prognostic value of androgen receptor (AR) and its related molecules in breast cancer is not well characterized. We retrospectively investigated 120 ER(+) and 120 ER(-) invasive breast cancers of 240 women, who were treated at our institution between January 2008 and December 2009. We excluded in situ, recurrent, metastatic, and bilateral carcinomas as well as non-epithelial lesions. Median follow-up was 74 months. Immunohistochemical assessment of expression of AR and metastasis-associated protein-1 (MTA1) resulted in 59.2 % (n = 142) AR(+) and 36.7 % (n = 88) high MTA1 expressing (MTA1(High)) carcinomas. MTA1(High) tumors were significantly more often ER(-), while AR(+) tumors were significantly more often HER2(+) (p < 0.01). MTA1(High)/ER(-) tumors were more often AR(-)/HER2(-) (p < 0.01). Patients with an AR(+)/ER(+) tumor had better disease-free survival (DFS; p = 0.011). Patients with an ER(-)/MTA1(High) tumor had significantly shorter DFS (p = 0.006) as well as patients with an AR(+)/HER2(+) tumor (p < 0.01). In Cox models, AR expression (HR, 0.248; 95 % CI, 0.086-0.716) and lymph node status (HR, 6.401; 95 % CI, 1.428-28.686) were independent predictors for DFS in ER(+) cancers, whereas AR(+)/HER2(+) expression status (HR, 2.927; 95 % CI, 1.256-6.821) and lymph node status (HR, 2.690; 95 % CI, 1.041-7.840) were independent predictors for DFS in ER(-) cancers. We show that AR might be an additional marker for endocrine responsiveness in ER(+) cancers and suggests that blocking MTA1 might be an effective way to inhibit AR/HER2 signaling in ER(-) breast cancer.

Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1- targeted chemopreventive and therapeutic efficacy of pterostilbene, a natural potent analog of resveratrol, in pre-clinical models of prostate cancer. Here, we show that high levels of MTA1 expression in Pten-loss prostate cooperate with key oncogenes, including c-Myc and Akt among others, to promote prostate cancer progression. Loss-of-function studies using human prostate cancer cells indicated direct involvement of MTA1 in inducing inflammation and epithelial-to-mesenchymal transition. Importantly, pharmacological inhibition of MTA1 by pterostilbene resulted in decreased proliferation and angiogenesis and increased apoptosis. This restrained prostatic intraepithelial neoplasia (PIN) formation in prostate-specific Pten heterozygous mice and reduced tumor development and progression in prostate-specific Pten-null mice. Our findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression. More significantly, it offers pre-clinical proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer.

Background: Metastasis-associated protein 1 (MTA1) plays an important role in tumourigenesis and progression of certain cancer types. In the current study, we analyzed the relationship between MTA1 expression and disease progression of colorectal cancer (CRC)., Materials and Methods: CRC tissues (n=93) and adjacent normal colorectal tissues (n=70) were analyzed by quantitative real-time polymerase chain reaction. MTA1 knockdown was established in RKO and HT115 cells using MTA1 siRNA., Results: The expression of MTA1 was significantly increased in CRC tissues compared to paired normal colorectal tissues, but decreased expression of MTA1 was correlated with poor prognosis (higher lymph node involvement stage, TNM stage, local invasion and recurrence) that was associated with increased expression of VEGFC and -D and the receptor VEGFR3., Conclusion: MTA1 is up-regulated in CRC. MTA1 expression is inversely associated with lymphatic metastases and the expression of VEGFC, VEGFD and VEGFR3., (Copyright© 2015, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.)

Granulomatosis with polyangiitis is a rare chronic inflammatory disease. In this multisystem autoimmune disorder neutrophils cause small vessels necrosis and infiltrate perivascular tissue to form granulomas. Progression of the disease is evaluated by the symptoms score and by a titer of anti-neutrophil cytoplasm antibodies. Despite glucocorticoid and immunosuppressive therapy, prognosis is complicated by chronic renal insufficiency, hearing loss and skin ulceration. In this preliminary study we tested the hypothesis that altered neutrophil expression of miRNAs can contribute to the cell activation, extracellular traps formation and decreased apoptosis. First we compared a profile of 728 miRNAs expressed in circulating neutrophils of patients with active disease and matched healthy donors. Subsequently, candidate miRNAs were quantified in neutrophils from 16 subjects with active disease, 16 asymptomatic patients at the remission and in 16 healthy controls. Out of 11 candidate miRNAs, only miR-128-3p was both biologically (relative quantity < 30% control or remission patients) and statistically (p<0.01) decreased in the cells during active stage of the disease. This miRNA correlated with a clinical score of the disease well. A set of 10 transcripts involved in the mechanism of the disease was quantified from the same neutrophils RNA. Relative expression of MMP9 was higher in neutrophils from the patients with active disease and correlated negatively with miR-128-3p. The opposite finding was present for MTA1 transcripts. Despite surprisingly scarce changes in the expression of neutrophil miRNAs, miR-128-3p is the best candidate for deciphering etiology of granulomatosis with polyangiitis.

The treatment of pancreatic cancer frequently fails due to local recurrence and hepatic metastasis. Our previous study found that Gd@C82(OH)22 can suppress pancreatic cancer by inhibiting MMP-2/9 expression. In this study, we further explored the epigenetic mechanism of Gd@C82(OH)22 in human pancreatic cancer metastasis. Gd@C82(OH)22 suppressed tumor metastasis through down-regulation of metastasis-associated protein 1 (MTA1), HDAC1, HIF-1α, and MMP-2/9 and up-regulation of reversion-cysteine protein with the Kazal motif (RECK). The level of acetylation was increased in the promoter region of the RECK gene after Gd@C82(OH)22 treatment. The interaction of MTA1, HDAC1, and HIF-1α was inhibited by Gd@C82(OH)22. Furthermore, large-scale molecular dynamics simulations revealed Gd@C82(OH)22 could serve as an effective HDAC inhibitor to the protein-protein association between HDAC1 and MTA1, especially through MTA1's SANT and ELM2 dimerization domains. Our findings implicate Gd@C82(OH)22 as a novel HDAC inhibitor acting to increase RECK expression by suppressing the MTA1/HDAC1 co-repressor complex. Gd@C82(OH)22 may serve as a potential HDAC1 inhibitor to suppress pancreatic cancer cell invasion and metastasis both in vitro and in vivo. According to computer analysis and experimental validation, Gd@C82(OH)22 activates RECK expression by inhibiting the interaction of HDAC1 and MTA1.

Background: Metastasis associated gene-1 (MTA1), was initially discovered in aggressive human cancer cell lines and has been subsequently associated with the invasiveness and metastatic potential of cancer cells., Materials and Methods: In the present study, we evaluated the expression levels of MTA1 in a cohort of human pituitary tumors (n=95) and examined the relationship between MTA1 expression and the pathological, clinical and aggressiveness of these tumors., Results: MTA1 was expressed at significantly higher levels in large tumors and in those with higher tumor grade. It was also observed that tumors that had invaded the suprasellar bones and tumors that destructed the sella had significantly higher levels than those without bone involvement (p<005). Although there did not appear to exist any relationship between MTA1 and cystic lesions in the tumors, endocrine-active tumors, namely those secreting prolactin, growth hormone, Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) had significantly lower MTA1 transcript levels than inactive tumors., Conclusion: MTA1 is associated with the aggressive nature of pituitary tumors and may be a potential therapeutic target in this tumor type., (Copyright© 2015, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.)

Metastasis-associated protein 1 (MTA1) and its short form (MTA1s) regulate the function of estrogen receptors (ERs). Estrogens, via ERs, affect placental growth and fetal development, a process that may involve MTA1 signaling. Expression of MTA1, MTA1s, ERα, and ERβ genes and proteins in rat placentas was studied on 16, 19, and 21 days of gestation (dg). The ERβ messenger RNA decreased significantly toward the end of gestation, whereas its protein level increased in the nuclear fraction on 21 dg. Both MTA1 and MTA1s increased with gestation. Decidual, trophoblast giant, glycogen, and villous trophoblast cells expressed MTA1, ERα, and ERβ proteins on all dg with colocalization of MTA1 with ERα and ERβ in the nucleus and cytoplasm. Expression of MTA1 suggests a possible role in regulating placental functions; considering the repressive function of MTA1 on ERs, the expression of MTA1 suggests that placental cells may be less sensitive to estrogens during late pregnancy., (© The Author(s) 2014.)

Metastasis associated protein 1 (MTA1) is a component of the nucleosome remodeling and deacetylating (NuRD) complex which mediates gene silencing and is overexpressed in several cancers. We reported earlier that resveratrol, a dietary stilbene found in grapes, can down-regulate MTA1. In the present study, we show that PTEN is inactivated by MTA1 in prostate cancer cells. Further, we show that resveratrol promotes acetylation and reactivation of PTEN via inhibition of the MTA1/HDAC complex, resulting in inhibition of the Akt pathway. In addition, we show that MTA1 knockdown is sufficient to augment acetylation of PTEN indicating a crucial role of MTA1 itself in the regulation of PTEN acetylation contributing to its lipid phosphatase activity. Acetylated PTEN preferentially accumulates in the nucleus where it binds to MTA1. We also show that MTA1 interacts exclusively with PTEN acetylated on Lys¹²⁵ and Lys¹²⁸, resulting in diminished p-Akt levels. Finally, using orthotopic prostate cancer xenografts, we demonstrate that both resveratrol treatment and MTA1 knockdown enhance PTEN levels leading to a decreased p-Akt expression and proliferation index. Taken together, our results indicate that MTA1/HDAC unit is a negative regulator of PTEN which facilitates survival pathways and progression of prostate cancer and that resveratrol can reverse this process through its MTA1 inhibitory function., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In the current study, for the first time, we found that metastasis-associated gene 1 (MTA1) was a higher-order chromatin structure organizer that decondenses the interphase chromatin and mitotic chromosomes. MTA1 interacts dynamically with nucleosomes during the cell cycle progression, prominently contributing to the mitotic chromatin/chromosome structure transitions at both prophase and telophase. We showed that the decondensation of interphase chromatin by MTA1 was independent of Mi-2 chromatin remodeling activity. H1 was reported to stabilize the compact higher-order chromatin structure through its interaction with DNA. Our data showed that MTA1 caused a reduced H1-chromatin interaction in-vivo. Moreover, the dynamic MTA1-chromatin interaction in the cell cycle contributed to the periodical H1-chromatin interaction, which in turn modulated chromatin/chromosome transitions. Although MTA1 drove a global decondensation of chromatin structure, it changed the expression of only a small proportion of genes. After MTA1 overexpression, the up-regulated genes were distributed in clusters along with down-regulated genes on chromosomes at parallel frequencies., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Themetastasis-associated gene 1 (MTA1) oncogene hasbeen suggested to be involved in the regulation of cancer progression. However, there is still no direct evidence that MTA1 regulates cisplatin (CDDP) resistance, as well as cancer stem cell properties. In this study, we found that MTA1 was enriched in CNE1/CDDP cells. Knock down of MTA1 in CNE1/CDDP cells reversed CSCs properties and CDDP resistance. However, ectopic expression of MTA1 in CNE1 cells induced CSCs phenotypes and CDDP insensitivity. Interestingly, ectopic overexpression of MTA1-induced CSCs properties and CDDP resistance were reversed in CNE1 cells after inhibition of PI3K/Akt by LY294002. In addition, MTA1 expression and Akt activity in CNE1/CDDP cells was much higher than that in CNE1 cells. These results suggested that MTA1 may play a critical role in promoting CDDP resistance in NPC cells by regulatingcancer stem cell properties via thePI3K/Akt signaling pathway. Our findings suggested that MTA1 may be a potential target for overcoming CDDP resistance in NPC therapy.

The nucleosome remodeling and deacetylase (NuRD) complex is a widely conserved transcriptional co-regulator that harbors both nucleosome remodeling and histone deacetylase activities. It plays a critical role in the early stages of ES cell differentiation and the reprogramming of somatic to induced pluripotent stem cells. Abnormalities in several NuRD proteins are associated with cancer and aging. We have investigated the architecture of NuRD by determining the structure of a subcomplex comprising RbAp48 and MTA1. Surprisingly, RbAp48 recognizes MTA1 using the same site that it uses to bind histone H4, showing that assembly into NuRD modulates RbAp46/48 interactions with histones. Taken together with other results, our data show that the MTA proteins act as scaffolds for NuRD complex assembly. We further show that the RbAp48-MTA1 interaction is essential for the in vivo integration of RbAp46/48 into the NuRD complex., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Hepatitis B virus (HBV) is a well-known hepadnavirus with a double-stranded circular DNA genome. Although HBV was first described approximately 50 years ago, the precise mechanisms of HBV infection and effective therapeutic strategies remain unclear. Here, we focus on summarizing the complicated mechanisms of HBV replication and infection, as well as genomic factors and epigenetic regulation. Additionally, we discuss in vivo models of HBV, as well as diagnosis, prevention and therapeutic drugs for HBV. Together, the data in this 50-year review may provide new clues to elucidate molecular mechanisms of HBV pathogenesis and shed new light on the future HBV therapies., (Copyright © 2013 Elsevier Ltd. All rights reserved.)