HGNC Approved Gene Symbol: MTA1
Cytogenetic location: 14q32.33 Genomic coordinates (GRCh38) : 14:105,419,827-105,470,729 (from NCBI)
MTA1 is a component of the chromatin remodeling complex that influences gene transcription by modulating target gene chromatin. MTA1 is widely upregulated in many carcinomas (summary by Reddy et al., 2009).
Toh et al. (1994) analyzed a candidate metastasis-associated gene, Mta1, which was isolated by differential cDNA library screening using the 13762NF rat mammary adenocarcinoma metastatic system. Northern blot analyses showed that Mta1 mRNA expression was 4-fold higher in the highly metastatic cell line MTLn3 than in the nonmetastatic cell line MTC.4. The Mta1 gene was expressed in various normal rat organs, especially in testis. The mRNA expression levels of the human MTA1 gene also correlated with the metastatic potential in 2 human breast cancer metastatic systems. MTA1 was expressed as an approximately 3-kb transcript. The full-length rat Mta1 cDNA sequence contains an ORF encoding a protein with several possible phosphorylation sites and a proline-rich stretch at the C-terminal end that matches the consensus sequence for the Src (190090) homology 3 (SH3) domain-binding motif. Western blot analyses using antibodies raised against glutathione S-transferase-Mta1 fusion protein or a synthetic oligopeptide showed that the levels of the Mta1 protein correlated with metastatic potential, results similar to those obtained from the Northern blot analyses.
Using rat Mta1 to screen a human melanoma cell line cDNA library, followed by 5-prime RACE, Nawa et al. (2000) cloned human MTA1. The deduced 715-amino acid protein has a calculated molecular mass of about 82 kD. It has a leucine zipper motif, followed by a GATA (see 305371)-type zinc finger motif, 3 nuclear localization signals, and a proline-rich motif near the C terminus. Rat and human MTA1 proteins share 96% identity. Northern blot analysis detected variable MTA1 expression in a variety of human cell lines. Immunofluorescence analysis revealed punctuate nuclear MTA1 staining, with exclusion from nucleoli. Western blot analysis detected MTA1 at an apparent molecular mass of 83 kD. Southern blot analysis detected MTA1 orthologs in several mammals, chicken, and yeast.
Xue et al. (1998) reported a novel human complex, named NURD for 'nucleosome remodeling and histone deacetylation,' which contains not only ATP-dependent nucleosome disruption activity, but also histone deacetylase activity, which usually associates with transcriptional repression. They identified 1 subunit of NURD as MTA1, a metastasis-associated protein with a region similar to the nuclear receptor corepressor NCOR (600849).
Zhang et al. (1999) showed that MTA2 (MTA1L1; 603947) and the 32-kD MBD3 (603573) protein are subunits of the NURD complex. Immunoprecipitation analysis showed that MBD3 interacts with HDAC1 (601241), RBBP4 (602923), and RBBP7 (300825), but not with MI2 (CHD4; 603277), suggesting that MBD3 is embedded within the NURD complex. The authors found that MTA2 directs the assembly of an active histone deacetylase complex and that the association of MTA2 with the complex requires MBD3. Gel mobility shift analysis determined that both NURD and MBD3 are unable to bind to methylated DNA in the absence of MBD2 (603547). Zhang et al. (1999) proposed that NURD is involved in the transcriptional repression of methylated DNA. Wade et al. (1999) also identified MTA1, MTA1L, and MBD3 as components of the NURD complex, which they referred to as the MI2 complex.
Mazumdar et al. (2001) showed that MTA1 is inducible by the beta-1 variant of heregulin (HRG, or NRG1; 142445). Stimulation of cells by HRG was accompanied by suppression of histone acetylation and enhancement of deacetylase activity. MTA1 in turn corepressed estrogen receptor element transcription and blocked the ability of estradiol to stimulate estrogen receptor (ESR1; 133430)-mediated transcription. Immunoprecipitation and Western blot analysis indicated that MTA1 directly interacts with HDAC1 and HDAC2 (605164) and with the activation domain of ESR1. Expression of MTA1 led to enhanced invasiveness and colony formation. Mazumdar et al. (2001) concluded that MTA1 targets ESR-mediated transcription and that HDAC complexes associated with the MTA1 corepressor may mediate ESR transcriptional repression by HRG.
Kumar et al. (2002) identified a naturally occurring short form of MTA1, which they called MTA1s, that contains a theretofore unknown sequence of 33 amino acids with an estrogen receptor-binding motif, leu-arg-ile-leu-leu (LRILL). MTA1s localizes in the cytoplasm, sequesters estrogen receptor in the cytoplasm, and enhances nongenomic responses of estrogen receptor. Deletion of the LRILL motif in MTA1s abolished its corepressor function and its interaction with estrogen receptor, and restored nuclear localization of estrogen receptor. Dysregulation of human epidermal growth factor receptor-2 (HER2; 164870) in breast cancer cells enhanced the expression of MTA1s and the cytoplasmic sequestration of estrogen receptor. Expression of MTA1s in breast cancer cells prevented ligand-induced nuclear translocation of estrogen receptor and stimulated malignant phenotypes. MTA1s expression is increased in human breast tumors with no or low nuclear estrogen receptor. The regulation of the cellular localization of estrogen receptor by MTA1s represents a mechanism for redirecting nuclear receptor signaling by nuclear exclusion.
Talukder et al. (2003) determined that MTA1 interacts with MAT1 (602659) both in vitro and in vivo. The N-terminal ring finger domain of MAT1 bound to the C-terminal GATA domain and the N-terminal bromodomain of MTA1. MTA1 deregulation in breast cancer cells resulted in its interaction with the estrogen receptor (ER; see 133430), HDAC2 (605164), and the multisubunit complex CAK (see 601953), which includes MAT1. MTA1 inhibited CAK stimulation of ER transactivation, and this inhibition was partially relieved by an HDAC inhibitor, suggesting that MTA1 might inhibit CAK-induced transactivation of ER by recruiting HDAC. Overexpression of MTA1 also inhibited the ability of the CAK complex to phosphorylate ER. Talukder et al. (2003) concluded that the transactivation function of ER might be influenced by the regulatory interactions between CAK and MTA1 in breast cancer cells.
Following enforced expression in a fibrosarcoma cell line, Yan et al. (2003) determined that MTA1 reduced basal and phorbol ester-induced expression of matrix metalloproteinase-9 (MMP9; 120361) at both the protein and mRNA level. DNase I hypersensitivity and restriction enzyme accessibility assays revealed involvement of multiple regions of the MMP9 promoter. Chromatin immunoprecipitation assays demonstrated MTA1 binding to the distal region, which spans several regulatory cis elements. Coimmunoprecipitation and chromatin immunoprecipitation assays revealed HDAC2-MTA1 interactions and the MTA1-dependent recruitment of HDAC2 to the distal MMP9 promoter region, resulting in diminished histone H3/H4 acetylation. MTA1 expression did not influence HDAC2 binding and H3/H4 acetylation at the proximal MMP9 promoter region. Inclusion of an HDAC inhibitor only partially relieved MTA1-repressed MMP9 expression, indicating a HDAC-insensitive component. Yan et al. (2003) concluded that MTA1 binds to the MMP9 promoter and thereby represses expression via histone-dependent and -independent mechanisms.
Zhang et al. (2005) found that MTA1 was a MYC (190080) target in human diploid fibroblasts and in human cancer cells. Endogenous MYC bound to the genomic MTA1 locus and recruited transcriptional coactivators. Short hairpin RNA (shRNA)-mediated knockdown of MTA1 blocked the ability of MYC to transform mammalian cells. The authors concluded that MTA1 within the NURD complex is one of the first downstream MYC targets and is essential for the transformation potential of MYC.
Using a functional genomic screen, Gururaj et al. (2006) identified BCAS3 (607470), a gene amplified and overexpressed in breast cancers, as a chromatin target of MTA1. MTA1 stimulation of BCAS3 transcription required ESR1 and involved a functional estrogen response element half-site in BCAS3. Furthermore, MTA1 was acetylated on lys626, and this acetylation was necessary for productive transcriptional recruitment of RNA polymerase II complex to the BCAS3 enhancer sequence. BCAS3 expression was elevated in mammary tumors from MTA1 transgenic mice and in 60% of human breast tumors, and it correlated with coexpression of MTA1 as well as with tumor grade and proliferation of primary breast tumor cultures.
By database analysis, Reddy et al. (2009) identified putative binding sites for microRNA-661 (MIR661; 613716) in the 3-prime UTR of MTA1. Western blot analysis, chromatin immunoprecipitation analysis, electrophoretic mobility shift assays, and reporter gene assays confirmed that MIR661 bound the 3-prime UTR of MTA1 and downregulated its expression. Reddy et al. (2009) also showed that CEBP-alpha (CEBPA; 116897) upregulated MIR661 expression in transfected HeLa and MDA-231 breast cancer cells. Expression of CEBP-alpha and MIR661 was inversely proportional to that of MTA1 in breast cancer cell lines, and the level of MTA1 protein was progressively upregulated with increasing metastatic potential. Overexpression of MIR661 in MDA-231 breast cancer cells inhibited cell motility, invasiveness, and anchorage-independent growth, and it reduced their ability to form tumors in a xenograft model. Reddy et al. (2009) concluded that MIR661 is a critical regulator of MTA1 expression.
By fluorescence in situ hybridization, Cui et al. (2001) mapped the MTA1 gene to chromosome 14q32.3. By the same method, Cui et al. (2001) mapped the mouse Mta1 gene to chromosome 12F.
Cui, Q., Matsusue, K., Toh, Y., Kono, A., Takiguchi, S. Assignment of the metastasis-associated gene (Mta1) to mouse chromosome band 12F and the metastasis-associated gene 2 (Mta2) to mouse chromosome band 19B by fluorescence in situ hybridization. Cytogenet. Cell Genet. 94: 246-247, 2001. [PubMed: 11856890] [Full Text: https://doi.org/10.1159/000048825]
Cui, Q., Takiguchi, S., Matsusue, K., Toh, Y., Yoshida, M. A. Assignment of the human metastasis-associated gene 1 (MTA1) to human chromosome band 14q32.3 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 93: 139-140, 2001. [PubMed: 11474200] [Full Text: https://doi.org/10.1159/000056969]
Gururaj, A. E., Singh, R. R., Rayala, S. K., Holm, C., den Hollander, P., Zhang, H., Balasenthil, S., Talukder, A. H., Landberg, G., Kumar, R. MTA1, a transcriptional activator of breast cancer amplified sequence 3. Proc. Nat. Acad. Sci. 103: 6670-6675, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 110: 4147 only, 2013. [PubMed: 16617102] [Full Text: https://doi.org/10.1073/pnas.0601989103]
Kumar, R., Wang, R.-A., Mazumdar, A., Talukder, A. H., Mandal, M., Yang, Z., Bagheri-Yarmand, R., Sahin, A., Hortobagyi, G., Adam, L., Barnes, C. J., Vadlamudi, R. K. A naturally occurring MTA1 variant sequesters oestrogen receptor-alpha in the cytoplasm. Nature 418: 654-657, 2002. [PubMed: 12167865] [Full Text: https://doi.org/10.1038/nature00889]
Mazumdar, A., Wang, R.-A., Mishra, S. K., Adam, L., Bagheri-Yarmand, R., Mandal, M., Vadlamudi, R. K., Kumar, R. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nature Cell Biol. 3: 30-37, 2001. [PubMed: 11146623] [Full Text: https://doi.org/10.1038/35050532]
Nawa, A., Nishimori, K., Lin, P., Maki, Y., Moue, K., Sawada, H., Toh, Y., Fumitaka, K., Nicolson, G. L. Tumor metastasis-associated human MTA1 gene: its deduced protein sequence, localization, and association with breast cancer cell proliferation using antisense phosphorothioate oligonucleotides. J. Cell. Biochem. 79: 202-212, 2000. [PubMed: 10967548]
Reddy, S. D. N., Pakala, S. B., Ohshiro, K., Rayala, S. K., Kumar, R. MicroRNA-661, a c/EBP-alpha target, inhibits metastatic tumor antigen 1 and regulates its functions. Cancer Res. 69: 5639-5642, 2009. [PubMed: 19584269] [Full Text: https://doi.org/10.1158/0008-5472.CAN-09-0898]
Talukder, A. H., Mishra, S. K., Mandal, M., Balasenthil, S., Mehta, S., Sahin, A. A., Barnes, C. J., Kumar, R. MTA1 interacts with MAT1, a cyclin-dependent kinase-activating kinase complex ring finger factor, and regulates estrogen receptor transactivation functions. J. Biol. Chem. 278: 11676-11685, 2003. [PubMed: 12527756] [Full Text: https://doi.org/10.1074/jbc.M209570200]
Toh, Y., Pencil, S. D., Nicolson, G. L. A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines: cDNA cloning, expression, and protein analyses. J. Biol. Chem. 269: 22958-22963, 1994. [PubMed: 8083195]
Wade, P. A., Gegonne, A., Jones, P. L., Ballestar, E., Aubry, F., Wolffe, A. P. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genet. 23: 62-66, 1999. [PubMed: 10471500] [Full Text: https://doi.org/10.1038/12664]
Xue, Y., Wong, J., Moreno, G. T., Young, M. K., Cote, J., Wang, W. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Molec. Cell 2: 851-861, 1998. [PubMed: 9885572] [Full Text: https://doi.org/10.1016/s1097-2765(00)80299-3]
Yan, C., Wang, H., Toh, Y., Boyd, D. D. Repression of 92-kDa type IV collagenase expression by MTA1 is mediated through direct interactions with the promoter via a mechanism, which is both dependent on and independent of histone deacetylation. J. Biol. Chem. 278: 2309-2316, 2003. [PubMed: 12431981] [Full Text: https://doi.org/10.1074/jbc.M210369200]
Zhang, X., DeSalle, L. M., Patel, J. H., Capobianco, A. J., Yu, D., Thomas-Tikhonenko, A., McMahon, S. B. Metastasis-associated protein 1 (MTA1) is an essential downstream effector of the c-MYC oncoprotein. Proc. Nat. Acad. Sci. 102: 13968-13973, 2005. [PubMed: 16172399] [Full Text: https://doi.org/10.1073/pnas.0502330102]
Zhang, Y., Ng, H.-H., Erdjument-Bromage, H., Tempst, P., Bird, A., Reinberg, D. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13: 1924-1935, 1999. [PubMed: 10444591] [Full Text: https://doi.org/10.1101/gad.13.15.1924]