The Experts below are selected from a list of 25395 Experts worldwide ranked by ideXlab platform
Rakesh Kumar - One of the best experts on this subject based on the ideXlab platform.
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MTA1 regulation of ERβ pathway in salivary gland carcinoma cells.
Biochemical and biophysical research communications, 2015Co-Authors: Kazufumi Ohshiro, Rakesh KumarAbstract:Abstracts: Although Metastatic-tumor antigen 1 (MTA1) is differentially expressed in metastatic cancer and coregulates the status and activity of nuclear receptors, its role upon estrogen receptor β (ERβ) – a potent tumor suppressor, remains poorly understood. Here we investigated whether MTA1 regulates the expression and functions of ERβ, an ER isoform predominantly expressed in salivary gland cancer cells. We found that the depletion of the endogenous MTA1 in the HSG and HSY salivary duct carcinoma cell lines enhances the expression of ERβ while MTA1 overexpression augmented the expression of ERβ in salivary duct carcinoma cells. Furthermore, MTA1 knockdown inhibited the proliferations and invasion of HSG and HSY cells. The noted ERβ downregulation by MTA1 overexpression involves the process of proteasomal degradation, as a proteasome inhibitor could block it. In addition, both MTA1 knockdown and ERβ overexpression attenuated the cell migration and inhibited the ERK1/2 signaling in the both cell lines. These findings imply that MTA1 dysregulation in a subset of salivary gland cancer might promote aggressive phenotypes by compromising the tumor suppressor activity of ERβ, and hence, MTA1-ERβ axis might serve a new therapeutic target for the salivary gland cancer. - Highlights: • MTA1 silencing upregulates ERβ expression in salivarymore » gland carcinoma cells. • MTA1 overexpression downregulates ERβ expression via proteasomal degradation. • Upregulation of ERβ expression inhibits cell migration and ERK signaling. • MTA1 knockdown inhibits cell proliferation and invasion.« less
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Role of MTA1 in cancer progression and metastasis
Cancer and Metastasis Reviews, 2014Co-Authors: Rakesh KumarAbstract:The MTA1 protein contributes to the process of cancer progression and metastasis through multiple genes and protein targets and interacting proteins with roles in transformation, anchorage-independent growth, invasion, survival, DNA repair, angiogenesis, hormone independence, metastasis, and therapeutic resistance. Because the roles and clinical significance of MTA proteins in human cancer are discussed by other contributors in this issue, this review will focus on our current understanding of the underlying principles of action behind the biological effects of MTA1. MTA proteins control a spectrum of cancer-promoting processes by modulating the expression of target genes and/or the activity of MTA-interacting proteins. In the case of MTA1, these functions are manifested through posttranslational modifications of MTA1 in response to upstream signals, MTA1 interaction with binding proteins, and the expression of target gene products. Studies delineating the molecular basis of dual functionality of MTA1 reveal that the functions of MTA1-chromatin-modifying complexes in the context of target gene regulation are dynamic in nature. The nature and targets of MTA1-chromatin-modifying complexes are also governed by the dynamic plasticity of the nucleosome landscape as well as kinetics of activation and inactivation of enzymes responsible for posttranslational modifications on the MTA1 protein. These broadly applicable functions also explain why MTA1 may be a “hub” gene in cancer. Because the deregulation of enzymes and their substrates with roles in MTA1 biology is not necessarily limited to cancer, we speculate that the lessons from MTA1 as a prototype dual master coregulator will be relevant for other human diseases. In this context, the concept of the dynamic nature of corepressor versus coactivator complexes and the MTA1 proteome as a function of time to signal is likely to be generally applicable to other multiprotein regulatory complexes in living systems.
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sumoylation and sumo interacting motif sim of metastasis tumor antigen 1 MTA1 synergistically regulate its transcriptional repressor function
Journal of Biological Chemistry, 2011Co-Authors: Lin Cong, Suresh B. Pakala, Kazufumi Ohshiro, Rakesh KumarAbstract:Metastasis tumor antigen 1 (MTA1), a component of the Mi-2·nucleosome remodeling and deacetylase complex, plays a crucial role in gene transcription, but the mechanism involved remains largely unknown. Here, we report that MTA1 is a substrate for small ubiquitin-related modifier 2/3 (SUMO2/3) in vivo. Protein inhibitor of activated STAT (PIAS) proteins enhance SUMOylation of MTA1 and may participate in paralog-selective SUMOylation, whereas sentrin/SUMO-specific protease 1 (SENP1) and 2 may act as deSUMOylation enzymes for MTA1. Moreover, MTA1 contains a functional SUMO-interacting motif (SIM) at its C terminus, and SIM is required for the efficient SUMOylation of MTA1. SUMO conjugation on Lys-509, which is located within the SUMO consensus site, together with SIM synergistically regulates the co-repressor activity of MTA1 on PS2 transcription, probably by recruiting HDAC2 onto the PS2 promoter. Interestingly, MTA1 may up-regulate the expression of SUMO2 via interaction with RNA polymerase II and SP1 at the SUMO2 promoter. These findings not only provide novel mechanistic insights into the regulation of the transcriptional repressor function of MTA1 by SUMOylation and SIM but also uncover a potential function of MTA1 in modulating the SUMOylation pathway.
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MTA1 coregulation of transglutaminase 2 expression and function during inflammatory response.
The Journal of biological chemistry, 2010Co-Authors: Krishna Sumanth Ghanta, Sirigiri Divijendra Natha Reddy, Suresh B. Pakala, Sujit S Nair, Rakesh KumarAbstract:Although both metastatic tumor antigen 1 (MTA1), a master chromatin modifier, and transglutaminase 2 (TG2), a multifunctional enzyme, are known to be activated during inflammation, it remains unknown whether these molecules regulate inflammatory response in a coordinated manner. Here we investigated the role of MTA1 in the regulation of TG2 expression in bacterial lipopolysaccharide (LPS)-stimulated mammalian cells. While studying the impact of MTA1 status on global gene expression, we unexpectedly discovered that MTA1 depletion impairs the basal as well as the LPS-induced expression of TG2 in multiple experimental systems. We found that TG2 is a chromatin target of MTA1 and of NF-κB signaling in LPS-stimulated cells. In addition, LPS-mediated stimulation of TG2 expression is accompanied by the enhanced recruitment of MTA1, p65RelA, and RNA polymerase II to the NF-κB consensus sites in the TG2 promoter. Interestingly, both the recruitment of p65 and TG2 expression are effectively blocked by a pharmacological inhibitor of the NF-κB pathway. These findings reveal an obligatory coregulatory role of MTA1 in the regulation of TG2 expression and of the MTA1-TG2 pathway, at least in part, in LPS modulation of the NF-κB signaling in stimulated macrophages.
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MTA1 coregulator regulates p53 stability and function.
The Journal of biological chemistry, 2009Co-Authors: Da Qiang Li, Suresh K Rayala, Sirigiri Divijendra Natha Reddy, Suresh B. Pakala, Yanping Zhang, Rakesh KumarAbstract:Although metastasis-associated protein 1 (MTA1) has recently been shown as a DNA damage responsive protein, the underlying mechanism for its role in DNA double-strand break (DSB) repair remains unknown. Here, we show that MTA1 controls p53 stability through inhibiting its ubiquitination by E3 ubiquitin ligases mouse double minute 2 (Mdm2) and constitutive photomorphogenic protein 1 (COP1). The underlying mechanisms involve the ability of MTA1 to compete with COP1 to bind to p53 and/or to destabilize COP1 and Mdm2. Consequently, MTA1 regulates the p53-dependent transcription of p53R2, a direct p53 target gene for supplying nucleotides to repair damaged DNA. Depletion of MTA1 impairs p53-dependent p53R2 transcription and compromises DNA repair. Interestingly, these events could be reversed by MTA1 reintroduction, indicating that MTA1 interjects into the p53-dependent DNA repair. Given the fact that MTA1 is widely up-regulated in human cancers, these findings in conjunction with our earlier finding of a crucial role of MTA1 in DSB repair suggest an inherent role of the MTA1-p53-p53R2 pathway in DNA damage response in cancer cells.
Haili Qian - One of the best experts on this subject based on the ideXlab platform.
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MTA1 promotes tumorigenesis and development of esophageal squamous cell carcinoma via activating the mek erk p90rsk signaling pathway
Carcinogenesis, 2020Co-Authors: Peng Nan, Haijuan Wang, Ting Wang, Jinsong Wang, Jingyao Zhang, Na Dou, Qimin Zhan, Haili QianAbstract:Metastasis-associated protein 1 (MTA1) is upregulated in multiple malignancies and promotes cancer proliferation and metastasis, but whether and how MTA1 promotes esophageal squamous cell carcinoma (ESCC) tumorigenesis remain unanswered. Here, we established an ESCC model in MTA1 transgenic mice induced by the chemical carcinogen 4-nitroquinoline 1-oxide (4-NQO) and found that MTA1 promotes ESCC tumorigenesis in mice. MTA1 overexpression was observed in ESCC cells and clinical ESCC samples. Overexpressed MTA1 increased colony formation and the invasiveness and migration of ESCC cells, whereas knock down of MTA1 in ESCC cells significantly decreased colony formation, invasion and migration in vitro and inhibited the growth of xenograft tumors in vivo. RNA sequencing (RNA-seq) analysis combined with western blot assays revealed that MTA1 promotes carcinogenesis by enhancing MEK/ERK/p90RSK signaling. The phosphorylation of MEK, ERK and their downstream target p90RSK was significantly decreased after MTA1 knockdown in ESCC cells and was increased in MTA1-overexpressing cells. Moreover, colony formation, invasion and migration potential were dramatically suppressed when cells overexpressing MTA1 were treated with MEK (PD0325901) or ERK (SCH772948) inhibitors. In conclusion, MTA1 plays a pivotal oncogenic role in ESCC tumorigenesis and development through activating the MEK/ERK/p90RSK pathway.
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a tgf β MTA1 sox4 ezh2 signaling axis drives epithelial mesenchymal transition in tumor metastasis
Oncogene, 2020Co-Authors: Jian Liu, Haijuan Wang, Haili Qian, Ting Wang, Hongsheng Xue, Qun Liu, Yantong Zhou, Tao WenAbstract:MTA1, SOX4, EZH2, and TGF-β are all potent inducers of epithelial-mesenchymal transition (EMT) in cancer; however, the signaling relationship among these molecules in EMT is poorly understood. Here, we investigated the function of MTA1 in cancer cells and demonstrated that MTA1 overexpression efficiently activates EMT. This activation resulted in a significant increase in the migratory and invasive properties of three different cancer cell lines through a common mechanism involving SOX4 activation, screened from a gene expression profiling analysis. We showed that both SOX4 and MTA1 are induced by TGF-β and both are indispensable for TGF-β-mediated EMT. Further investigation identified that MTA1 acts upstream of SOX4 in the TGF-β pathway, emphasizing a TGF-β-MTA1-SOX4 signaling axis in EMT induction. The histone methyltransferase EZH2, a component of the polycomb (PcG) repressive complex 2 (PRC2), was identified as a critical responsive gene of the TGF-β-MTA1-SOX4 signaling in three different epithelial cancer cell lines, suggesting that this signaling acts broadly in cancer cells in vitro. The MTA1-SOX4-EZH2 signaling cascade was further verified in TCGA pan-cancer patient samples and in a colon cancer cDNA microarray, and activation of genes in this signaling pathway predicted an unfavorable prognosis in colon cancer patients. Collectively, our data uncover a SOX4-dependent EMT-inducing mechanism underlying MTA1-driven cancer metastasis and suggest a widespread TGF-β-MTA1-SOX4-EZH2 signaling axis that drives EMT in various cancers. We propose that this signaling may be used as a common therapeutic target to control epithelial cancer metastasis.
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MTA1 regulates higher order chromatin structure and histone h1 chromatin interaction in vivo
Molecular Oncology, 2015Co-Authors: Haijuan Wang, Changzhi Huang, Chen Lin, Jian Liu, Yanan Chang, Jinlong Zhang, Jia Wang, Mei Zhao, Haili QianAbstract: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.
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MTA1 downregulation inhibits malignant potential in a small cell lung cancer cell line.
Oncology reports, 2014Co-Authors: Hongsheng Xue, Haijuan Wang, Chen Lin, Qimin Zhan, Jian Liu, Huan Liu, Li Han, Zhilong Zhao, Haili QianAbstract:As a component of the nuclear remodeling and deacetylation complex (NuRD complex), metastasis-associated gene 1 (MTA1) has been reported to play a key role in cancer malignancy. However, whether MTA1 functions in small cell lung cancer (SCLC) malignant behavior and whether it is feasible to be used as a therapeutic target have not been evaluated. The present study aimed to investigate the effects of MTA1 downregulation on SCLC malignancy. First we demonstrated the overexpression of MTA1 in SCLC specimens. After knocking down the MTA1 level by specific siRNA sequence, the biological consequences on proliferation, migration, invasion and apoptosis were evaluated. The results showed that MTA1 silencing had potent suppressive effects on SCLC proliferation, migration and invasion. Apoptosis but not cell cycle arrest was induced in the MTA1-silenced SCLC cells. In summary, MTA1 plays a critical role in regulating the malignant behaviors of SCLC. Depleting MTA1 level may be an effective strategy by which to suppress SCLC growth and metastasis in future biotherapeutic attempts.
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Subcellular localization of MTA proteins in normal and cancer cells
Cancer and Metastasis Reviews, 2014Co-Authors: Haijuan Wang, Changzhi Huang, Haili QianAbstract:The subcellular localization of a protein is closely linked to and indicates its function. The metastatic tumor antigen (MTA) family has been under continuous investigation since its identification two decades ago. MTA1, MTA2, and MTA3 are the main members of the MTA family. MTA1, as the representative member of this family, has been shown to be widely expressed in both embryonic and adult tissues, as well as in normal and cancerous conditions, indicating that MTA1 has functions both in physiological and pathological contexts. MTA1 is expressed at a higher level in most cancers than in their normal tissue counterparts. Even in normal cells, MTA1 levels vary a great deal from tissue to tissue. Importantly, MTA1 shows a multiple localization pattern in the cell, as do MTA2 and MTA3. Different MTA components in different subcellular compartments may exert different molecular functions in the cell. Previous studies revealed that MTA1 and MTA2 are predominately localized to the nucleus, while MTA3 is observed in both the nucleus and cytoplasm. Recent studies have reported that MTA1 is located in the nucleus, cytoplasm, and the nuclear envelope. In the nucleus, MTA1 dynamically interacts with chromatin in a MTA1-K532 methylation-dependent manner, whereas cytoplasmic MTA1 binds to the microtubule skeleton. MTA1 also shows a dynamic distribution during the cell cycle. Further investigations are needed to identify the exact subcellular localizations of MTA proteins. We review the sub-cellular localization patterns of the MTA family members and give a comprehensive overview of their respective molecular activities in multiple contexts.
Richard E. Leach - One of the best experts on this subject based on the ideXlab platform.
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MTA1 and mta3 regulate hif1a expression in hypoxia treated human trophoblast cell line htr8 svneo
Medical journal of obstetrics and gynecology, 2013Co-Authors: Kai Wang, Susan D Ferguson, Ying Chen, Richard E. LeachAbstract:: Hypoxia plays an important role in placental trophoblast differentiation and function during early pregnancy. Hypoxia-inducible factor 1 alpha (HIF1a) is known to regulate cellular adaption to hypoxic conditions. However, our current understanding of the role of HIF1a in trophoblast physiology is far from complete. Metastasis Associated Protein 1 and 3 (MTA1 and MTA3) are components of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a chromatin remodeling complex, and are highly expressed in term placental trophoblasts. However, the role of MTA1 and MTA3 in the hypoxic placental environment of early pregnancy is unknown. In the present study, we examined the association among MTA1, MTA3 and HIF1a expression under hypoxic conditions in trophoblasts both in vivo and in vitro. We first investigated the localization of MTA1 and MTA3 with HIF1a expression in the placental trophoblast of 1st trimester placenta via immunohistochemistry. Our data reveals that under physiologically hypoxic environment, MTA1 and MTA3 along with HIF1a are highly expressed by villous trophoblasts. Next, we investigated the effect of hypoxia on these genes in vitro using the first trimester-derived HTR8/SVneo cell line and observed up-regulation of MTA1 and MTA3 as well as HIF1a protein following hypoxia treatment. To investigate the direct effect of MTA1 and MTA3 upon HIF1a, we over-expressed MTA1 and MTA3 genes in HTR8/SVneo cells respectively and examined protein levels of HIF1a via Western blot as well as HIF1a target gene expression using a luciferase assay driven by a hypoxia-response element promoter (HRE-luciferase). We found that over-expressions of MTA1 and MTA3 up-regulate both HIF1a protein level and HRE-luciferase activity under hypoxic condition. In summary, both MTA1 and MTA3 are induced by hypoxia and up-regulate HIF1a expression and HIF1a target gene expression in trophoblasts. These data suggest that MTA1 and MTA3 play critical roles in trophoblast function and differentiation during early pregnancy.
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MTA1 and MTA3 Regulate HIF1a Expression in Hypoxia-Treated Human Trophoblast Cell Line HTR8/Svneo.
Medical journal of obstetrics and gynecology, 2013Co-Authors: Kai Wang, Susan D Ferguson, Ying Chen, Richard E. LeachAbstract:: Hypoxia plays an important role in placental trophoblast differentiation and function during early pregnancy. Hypoxia-inducible factor 1 alpha (HIF1a) is known to regulate cellular adaption to hypoxic conditions. However, our current understanding of the role of HIF1a in trophoblast physiology is far from complete. Metastasis Associated Protein 1 and 3 (MTA1 and MTA3) are components of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a chromatin remodeling complex, and are highly expressed in term placental trophoblasts. However, the role of MTA1 and MTA3 in the hypoxic placental environment of early pregnancy is unknown. In the present study, we examined the association among MTA1, MTA3 and HIF1a expression under hypoxic conditions in trophoblasts both in vivo and in vitro. We first investigated the localization of MTA1 and MTA3 with HIF1a expression in the placental trophoblast of 1st trimester placenta via immunohistochemistry. Our data reveals that under physiologically hypoxic environment, MTA1 and MTA3 along with HIF1a are highly expressed by villous trophoblasts. Next, we investigated the effect of hypoxia on these genes in vitro using the first trimester-derived HTR8/SVneo cell line and observed up-regulation of MTA1 and MTA3 as well as HIF1a protein following hypoxia treatment. To investigate the direct effect of MTA1 and MTA3 upon HIF1a, we over-expressed MTA1 and MTA3 genes in HTR8/SVneo cells respectively and examined protein levels of HIF1a via Western blot as well as HIF1a target gene expression using a luciferase assay driven by a hypoxia-response element promoter (HRE-luciferase). We found that over-expressions of MTA1 and MTA3 up-regulate both HIF1a protein level and HRE-luciferase activity under hypoxic condition. In summary, both MTA1 and MTA3 are induced by hypoxia and up-regulate HIF1a expression and HIF1a target gene expression in trophoblasts. These data suggest that MTA1 and MTA3 play critical roles in trophoblast function and differentiation during early pregnancy.
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MTA1 and mta3 regulate hif1a expression in hypoxia treated human trophoblast cell line
2013Co-Authors: Kai Wang, Richard E. Leach, Ying Chen, Susan D FergusonAbstract:Hypoxia plays an important role in placental trophoblast differentiation and function during early pregnancy. Hypoxia-inducible factor 1 alpha (HIF1a) is known to regulate cellular adaption to hypoxic conditions. However, our current understanding of the role of HIF1a in trophoblast physiology is far from complete. Metastasis Associated Protein 1 and 3 (MTA1 and MTA3) are components of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a chromatin remodeling complex, and are highly expressed in term placental trophoblasts. However, the role of MTA1 and MTA3 in the hypoxic placental environment of early pregnancy is unknown. In the present study, we examined the association among MTA1, MTA3 and HIF1a expression under hypoxic conditions in trophoblasts both in vivo and in vitro. We first investigated the localization of MTA1 and MTA3 with HIF1a expression in the placental trophoblast of 1st trimester placenta via immunohistochemistry. Our data reveals that under physiologically hypoxic environment, MTA1 and MTA3 along with HIF1a are highly expressed by villous trophoblasts. Next, we investigated the effect of hypoxia on these genes in vitro using the first trimester-derived HTR8/SVneo cell line and observed up-regulation of MTA1 and MTA3 as well as HIF1a protein following hypoxia treatment. To investigate the direct effect of MTA1 and MTA3 upon HIF1a, we over-expressed MTA1 and MTA3 genes in HTR8/SVneo cells respectively and examined protein levels of HIF1a via Western blot as well as HIF1a target gene expression using a luciferase assay driven by a hypoxia-response element promoter (HRE-luciferase). We found that over-expressions of MTA1 and MTA3 up-regulate both HIF1a protein level and HRE-luciferase activity under hypoxic condition. In summary, both MTA1 and MTA3 are induced by hypoxia and up-regulate HIF1a expression and HIF1a target gene expression in trophoblasts. These data suggest that MTA1 and MTA3 play critical roles in trophoblast function and differentiation during early pregnancy.
Anait S. Levenson - One of the best experts on this subject based on the ideXlab platform.
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MTA1 drives malignant progression and bone metastasis in prostate cancer.
Molecular oncology, 2018Co-Authors: Avinash Kumar, Swati Dhar, Nasir A. Butt, Gisella Campanelli, Jason Schallheim, Christian R. Gomez, Anait S. LevensonAbstract:Prostate cancer often metastasizes to the bone, leading to morbidity and mortality. While metastasis-associated protein 1 (MTA1) is highly overexpressed in metastatic tumors and bone metastatic lesions, its exact role in the development of metastasis is unknown. Here, we report the role of MTA1 in prostate cancer progression and bone metastasis in vitro and in vivo. We found that MTA1 silencing diminished formation of bone metastases and impaired tumor growth in intracardiac and subcutaneous prostate cancer xenografts, respectively. This was attributed to reduced colony formation, invasion, and migration capabilities of MTA1 knockdown cells. Mechanistic studies revealed that MTA1 silencing led to a significant decrease in the expression of cathepsin B (CTSB), a cysteine protease critical for bone metastasis, with an expected increase in the levels of E-cadherin in both cells and xenograft tumors. Moreover, meta-analysis of clinical samples indicated a positive correlation between MTA1 and CTSB. Together, these results demonstrate the critical role of MTA1 as an upstream regulator of CTSB-mediated events associated with cell invasiveness and raise the possibility that targeting MTA1/CTSB signaling in the tumor may prevent the development of bone metastasis in prostate cancer.
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Abstract 5107: A novel MTA1 knock-in mouse model for the mechanistic and therapeutic studies of MTA1-driven prostate cancer
Tumor Biology, 2018Co-Authors: Avinash Kumar, Swati Dhar, Nasir A. Butt, Pravin R. Phadatare, Kshiti Dholakia, Jogarao Vedula, Virginia Donovan, Anait S. LevensonAbstract:Metastasis-associated protein 1 is known to play role in prostate cancer progression and metastasis. Studies of MTA1-mediated prostate cancer tumorigenesis, progression and metastasis have been hampered by a lack of suitable experimental system. Here we describe a new conditional mouse model that shows strong MTA1 expression in the prostate. This model was generated through MTA1 transgene knocked into the mouse ROSA26 (R26) locus using CAG-LoxP-Stop-LoxP (LSL)-2HA-MTA1-T2A-GFP-pA construct (Applied StemCell,Inc, Menlo Park, CA). Briefly, after generation of a genetically modified founder mouse line Rosa26-3attP, resulted MTA1 transgene embryos were injected into foster mice to produce MTA1 founders, designated as R26-LSL-MTA1. To monitor tumor formation and development in live animals by using IVIS, we have crossbred R26-LSL-MTA1 with Pb-Cre+;Luc and generated transgenic lines that express MTA1 and Luc upon Cre-mediated removal of the LSL cassette, specifically in the prostate epithelium (Pb-Cre+;R26MTA1;R26Luc) (MTA1-tg). We confirmed prostate-specific expression of the MTA1 transgene on mRNA and protein levels. We evaluated prostate histology for differences in histology of control normal prostates (Pb-Cre-; MTA1-tg) and MTA1-tg mice at as early as 13-weeks of age. MTA1 overexpressing prostate showed signs of mPIN characterized by glandular structures composed of atypical proliferating luminal cells that fill out the lumen. We detected differences in cellular proliferation, as determined by increased PCNA and decreased p27 as well as Ki67 immunofluorescent staining in MTA1-tg prostate. Moreover, expression of several oncogenic MTA1-guided molecules was increased in the prostates of MTA1-tg mice. We have previously reported on the role of MTA1-mediated signaling in prostate tumor progression in the prostate-specific Pten heterozygous (Pb-Cre+; Pten+/f) and Pten null (Pb-Cre+; Ptenf/f ) mice. To determine the role of MTA1 overexpression in the context of PTEN loss, we generated MTA1-tg; Pten+/f and MTA1-tg; Ptenf/f mice to evaluate whether MTA1overexpression in the prostate promotes an earlier onset, greater total incidence, accelerated tumor growth rate and metastasis. We predict that MTA1 overexpression will cause higher activation of downstream pathways to promote cancer cell survival, which will result in increased incidence of invasive adenocarcinoma and probably lymph node metastasis. Mice will be sacrificed at different time points for prostate tissue and lymph nodes isolation and subsequent histopathological, immunochemical and molecular evaluation. Citation Format: Avinash Kumar, Swati Dhar, Nasir A. Butt, Pravin R. Phadatare, Kshiti Dholakia, Jogarao Vedula, Virginia Donovan, Anait S. Levenson. A novel MTA1 knock-in mouse model for the mechanistic and therapeutic studies of MTA1-driven prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5107.
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resveratrol regulates pten akt pathway through inhibition of MTA1 hdac unit of the nurd complex in prostate cancer
Biochimica et Biophysica Acta, 2015Co-Authors: Swati Dhar, Avinash Kumar, Guri Tzivion, Anait S. LevensonAbstract:Abstract 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 Lys 125 and Lys 128 , 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.
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MTA family of proteins in prostate cancer: biology, significance, and therapeutic opportunities
Cancer and Metastasis Reviews, 2014Co-Authors: Anait S. Levenson, Avinash Kumar, Xu ZhangAbstract:This review summarizes our current understanding of the role of MTA family members, particularly MTA1, with a special emphasis on prostate cancer. The interest for the role of MTA1 in prostate cancer was boosted from our initial findings of MTA1 as a component of “vicious cycle” and a member of bone metastatic signature. Analysis of human prostate tissues, xenograft and transgenic mouse models of prostate cancer, and prostate cancer cell lines has provided support for the role of MTA1 in advanced disease and its potential role in initial stages of prostate tumor progression. Recent discoveries have highlighted a critical role for MTA1 in inflammation-triggered prostate tumorigenesis, epithelial-to-mesenchymal transition, prostate cancer survival pathways, and site metastasis. Evidence for MTA1 as an upstream negative regulator of tumor suppressor genes such as p53 and PTEN has also emerged. MTA1 is involved in prostate tumor angiogenesis by regulating several pro-angiogenic factors. Evidence for MTA1 as a prognostic marker for aggressive prostate cancer and disease recurrence has been described. Importantly, pharmacological dietary agents, namely resveratrol and its analogs, are potentially applicable to prostate cancer prevention, treatment, and control of cancer progression due to their potent inhibitory effects on MTA proteins.
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Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1)
The Prostate, 2010Co-Authors: Li Kai, Jun Wang, Marina Ivanovic, Yeon Tae Chung, William B. Laskin, Frank T. Schulze-hoepfner, Yelena Mirochnik, Robert L. Satcher, Anait S. LevensonAbstract:BACKGROUND Metastasis-associated protein 1 (MTA1) is overexpressed in many forms of cancer types but its role in prostate cancer (PCa) progression and metastasis has not been explored. In this study, we addressed the functional and biological role of MTA1 in PCa. METHODS Gene expression profiling was used to determine MTA1 overexpression during PCa cell–bone interaction. Immunohistochemistry was used to detect MTA1 on tissue microarrays (TMA) and vascular endothelial growth factor (VEGF), CD31, and Ki67 in xenografts. We used retroviral or lentiviral RNAi transduction of PCa cells to establish MTA1 knockdowns. RT-PCR, Western blot, invasion, and endothelial cell migration assays were used to characterize the cells in vitro. The role of MTA1 in PCa tumorigenesis was evaluated in mouse xenografts. RESULTS We identified MTA1 as a component of bone metastasis signature in PCa, which suggested a possible role for MTA1 in PCa progression and metastasis. MTA1 was expressed at higher levels in PCa cell lines than in normal prostate epithelial cells. Silencing MTA1 significantly suppressed the invasion and angiogenic activity of the cells in vitro and delayed tumor formation and development in mouse xenografts. Tumors that express MTA1 had higher proliferative indices, secreted higher levels of VEGF and were more vascularized. Analysis of the human TMA showed positive correlation between MTA1 nuclear localization/staining intensity and PCa aggressiveness. CONCLUSIONS MTA1 pro-angiogenic and pro-invasive functions create permissive environment for PCa tumor growth and likely support metastasis. Taken together with its predictive values, MTA1 can be utilized both as a prognostic marker and a therapy target in PCa. Prostate 71:268–280, 2011. © 2010 Wiley-Liss, Inc.
Haijuan Wang - One of the best experts on this subject based on the ideXlab platform.
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MTA1 promotes tumorigenesis and development of esophageal squamous cell carcinoma via activating the mek erk p90rsk signaling pathway
Carcinogenesis, 2020Co-Authors: Peng Nan, Haijuan Wang, Ting Wang, Jinsong Wang, Jingyao Zhang, Na Dou, Qimin Zhan, Haili QianAbstract:Metastasis-associated protein 1 (MTA1) is upregulated in multiple malignancies and promotes cancer proliferation and metastasis, but whether and how MTA1 promotes esophageal squamous cell carcinoma (ESCC) tumorigenesis remain unanswered. Here, we established an ESCC model in MTA1 transgenic mice induced by the chemical carcinogen 4-nitroquinoline 1-oxide (4-NQO) and found that MTA1 promotes ESCC tumorigenesis in mice. MTA1 overexpression was observed in ESCC cells and clinical ESCC samples. Overexpressed MTA1 increased colony formation and the invasiveness and migration of ESCC cells, whereas knock down of MTA1 in ESCC cells significantly decreased colony formation, invasion and migration in vitro and inhibited the growth of xenograft tumors in vivo. RNA sequencing (RNA-seq) analysis combined with western blot assays revealed that MTA1 promotes carcinogenesis by enhancing MEK/ERK/p90RSK signaling. The phosphorylation of MEK, ERK and their downstream target p90RSK was significantly decreased after MTA1 knockdown in ESCC cells and was increased in MTA1-overexpressing cells. Moreover, colony formation, invasion and migration potential were dramatically suppressed when cells overexpressing MTA1 were treated with MEK (PD0325901) or ERK (SCH772948) inhibitors. In conclusion, MTA1 plays a pivotal oncogenic role in ESCC tumorigenesis and development through activating the MEK/ERK/p90RSK pathway.
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a tgf β MTA1 sox4 ezh2 signaling axis drives epithelial mesenchymal transition in tumor metastasis
Oncogene, 2020Co-Authors: Jian Liu, Haijuan Wang, Haili Qian, Ting Wang, Hongsheng Xue, Qun Liu, Yantong Zhou, Tao WenAbstract:MTA1, SOX4, EZH2, and TGF-β are all potent inducers of epithelial-mesenchymal transition (EMT) in cancer; however, the signaling relationship among these molecules in EMT is poorly understood. Here, we investigated the function of MTA1 in cancer cells and demonstrated that MTA1 overexpression efficiently activates EMT. This activation resulted in a significant increase in the migratory and invasive properties of three different cancer cell lines through a common mechanism involving SOX4 activation, screened from a gene expression profiling analysis. We showed that both SOX4 and MTA1 are induced by TGF-β and both are indispensable for TGF-β-mediated EMT. Further investigation identified that MTA1 acts upstream of SOX4 in the TGF-β pathway, emphasizing a TGF-β-MTA1-SOX4 signaling axis in EMT induction. The histone methyltransferase EZH2, a component of the polycomb (PcG) repressive complex 2 (PRC2), was identified as a critical responsive gene of the TGF-β-MTA1-SOX4 signaling in three different epithelial cancer cell lines, suggesting that this signaling acts broadly in cancer cells in vitro. The MTA1-SOX4-EZH2 signaling cascade was further verified in TCGA pan-cancer patient samples and in a colon cancer cDNA microarray, and activation of genes in this signaling pathway predicted an unfavorable prognosis in colon cancer patients. Collectively, our data uncover a SOX4-dependent EMT-inducing mechanism underlying MTA1-driven cancer metastasis and suggest a widespread TGF-β-MTA1-SOX4-EZH2 signaling axis that drives EMT in various cancers. We propose that this signaling may be used as a common therapeutic target to control epithelial cancer metastasis.
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MTA1 regulates higher order chromatin structure and histone h1 chromatin interaction in vivo
Molecular Oncology, 2015Co-Authors: Haijuan Wang, Changzhi Huang, Chen Lin, Jian Liu, Yanan Chang, Jinlong Zhang, Jia Wang, Mei Zhao, Haili QianAbstract: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.
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MTA1 downregulation inhibits malignant potential in a small cell lung cancer cell line.
Oncology reports, 2014Co-Authors: Hongsheng Xue, Haijuan Wang, Chen Lin, Qimin Zhan, Jian Liu, Huan Liu, Li Han, Zhilong Zhao, Haili QianAbstract:As a component of the nuclear remodeling and deacetylation complex (NuRD complex), metastasis-associated gene 1 (MTA1) has been reported to play a key role in cancer malignancy. However, whether MTA1 functions in small cell lung cancer (SCLC) malignant behavior and whether it is feasible to be used as a therapeutic target have not been evaluated. The present study aimed to investigate the effects of MTA1 downregulation on SCLC malignancy. First we demonstrated the overexpression of MTA1 in SCLC specimens. After knocking down the MTA1 level by specific siRNA sequence, the biological consequences on proliferation, migration, invasion and apoptosis were evaluated. The results showed that MTA1 silencing had potent suppressive effects on SCLC proliferation, migration and invasion. Apoptosis but not cell cycle arrest was induced in the MTA1-silenced SCLC cells. In summary, MTA1 plays a critical role in regulating the malignant behaviors of SCLC. Depleting MTA1 level may be an effective strategy by which to suppress SCLC growth and metastasis in future biotherapeutic attempts.
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Subcellular localization of MTA proteins in normal and cancer cells
Cancer and Metastasis Reviews, 2014Co-Authors: Haijuan Wang, Changzhi Huang, Haili QianAbstract:The subcellular localization of a protein is closely linked to and indicates its function. The metastatic tumor antigen (MTA) family has been under continuous investigation since its identification two decades ago. MTA1, MTA2, and MTA3 are the main members of the MTA family. MTA1, as the representative member of this family, has been shown to be widely expressed in both embryonic and adult tissues, as well as in normal and cancerous conditions, indicating that MTA1 has functions both in physiological and pathological contexts. MTA1 is expressed at a higher level in most cancers than in their normal tissue counterparts. Even in normal cells, MTA1 levels vary a great deal from tissue to tissue. Importantly, MTA1 shows a multiple localization pattern in the cell, as do MTA2 and MTA3. Different MTA components in different subcellular compartments may exert different molecular functions in the cell. Previous studies revealed that MTA1 and MTA2 are predominately localized to the nucleus, while MTA3 is observed in both the nucleus and cytoplasm. Recent studies have reported that MTA1 is located in the nucleus, cytoplasm, and the nuclear envelope. In the nucleus, MTA1 dynamically interacts with chromatin in a MTA1-K532 methylation-dependent manner, whereas cytoplasmic MTA1 binds to the microtubule skeleton. MTA1 also shows a dynamic distribution during the cell cycle. Further investigations are needed to identify the exact subcellular localizations of MTA proteins. We review the sub-cellular localization patterns of the MTA family members and give a comprehensive overview of their respective molecular activities in multiple contexts.