Disease relevance of MTA1

• Overexpression of MTA1 in breast-cancer cells is accompanied by enhancement of the ability of cells to invade and to grow in an anchorage-independent manner [1].
• The expression of metastasis-associated protein 1 (MTA1) correlates well with tumor metastases; however, the associated molecular mechanism is not fully understood [2].
• We observed that the expression of MTA1 was strongly induced under hypoxia in breast cancer cell lines such as MCF-7 and MDA-MB-231 [2].
• Here, we extend this observation to squamous carcinoma cells, which express high levels of MTA1 relative to normal or immortalized keratinocytes [3].
• The human metastasis-associated gene (MTA1), a member of the nucleosome remodeling complex with histone deacetylase activity, is frequently overexpressed in biologically aggressive epithelial neoplasms [3].

High impact information on MTA1

• The complex contains the histone deacetylases HDAC1/2, histone-binding proteins, the dermatomyositis-specific autoantigen Mi2beta, a polypeptide related to the metastasis-associated protein 1, and a novel polypeptide of 32 kDa [4].
• Upregulation of metastatic tumour antigen 1 (MTA1) is associated with the invasiveness and metastatic potential of several human cancers and acts as a co-repressor of nuclear ER-alpha [5].
• One subunit of NURD was identified as MTA1, a metastasis-associated protein with a region similar to the nuclear receptor core-pressor, N-CoR; and antibodies against NURD partially relieve transcriptional repression by thyroid hormone receptor [6].
• Activated human lymphocytes and aggressive non-Hodgkin's lymphomas express a homologue of the rat metastasis-associated variant of CD44 [7].
• MTA1 is also a potent corepressor of ERE transcription, as it blocks the ability of oestradiol to stimulate ER-mediated transcription [1].

Chemical compound and disease context of MTA1

• Experimental inhibition of MTA1 protein expression using antisense phosphorothioate oligonucleotides resulted in inhibition of growth and invasion of human MDA-MB-231 breast cancer cells with relatively high MTA1 expression [8].
• MTA1 (metastasis-associated protein 1) represses estrogen receptor-alpha-driven transcription by recruiting histone deacetylases (HDACs) to the estrogen response element containing target gene chromatin in breast cancer cells [9].
• Tamoxifen and/or anthracylcene-based chemotherapies eliminated all MTA1 associations with clinical outcome, suggesting MTA1 overexpression predicts early disease relapse, but sensitizes breast tumors to systemic therapies [10].
• However, MTA1 expression did not correlate with tumor stage, status of estrogen and progesterone receptors, or axillary lymph node metastasis [11].
• We have previously demonstrated that bcl-2 overexpression enhances the metastatic potential of the MCF7 ADR human breast cancer cell line resistant to adriamycin by inducing metastasis-associated properties [12].

Biological context of MTA1

• These results indicate that acetylation is the major target of MTA1/HDAC1 function [2].
• MTA2, which is homologous to MTA1, is a component of the NuRD ATP-dependent chromatin remodeling and histone deacetylase complex [13].
• These results establish that, in keratinocytes, MTA1 expression contributes to several aspects of the metastatic phenotype including survival in the anchorage independent state, migration, and invasion [3].
• In Caenorhabditis elegans, MTA1-like genes regulate cell polarity, migration, embryonic patterning, and vulva development [14].
• Recent studies have shown that growth factor stimulation of breast cancer cells induces the expression of MTA1 and its interaction with and repression of the estrogen receptor (ER) transactivation function, leading to enhanced anchorage-independent growth in vitro and hormone independence [14].

Anatomical context of MTA1

• Cancers overexpressing MTA1 protein invaded deeper into the esophageal wall (p < 0.005) and showed significantly higher degrees of lymph node metastasis (p < 0.01), higher pathological stage, more lymphatic involvement and poorer prognosis (p < 0.05) than the remaining cases [15].
• The intensities of immunostaining of MTA1 protein and acetylated histone H4 in carcinoma tissues (Ca) were compared to normal epithelium (N) contained in the same section [15].
• MTA1 was overexpressed in HCC cells versus nonmalignant hepatocytes in 31 of 45 HCC specimens (69%) [16].
• The results suggest that the MTA1 protein may serve multiple functions in cellular signaling, chromosome remodeling and transcription processes that are important in the progression, invasion and growth of metastatic epithelial cells [8].
• MAGE-D2 and MTA1 message were significantly elevated (> 10-fold, P < 0.01) in the malignant and goblet cell adenocarcinoid tumors but not in the appendicitis-associated carcinoids or normal mucosa [17].

Associations of MTA1 with chemical compounds

• The histone-deacetylase inhibitor trichostatin A blocks MTA1-mediated repression of ERE transcription [1].
• Furthermore, we discovered that MTA1 is acetylated on lysine 626, and that this acetylation is necessary for a productive transcriptional recruitment of RNA polymerase II complex to the BCAS3 enhancer sequence [18].
• MTA1 dysregulation in mammary epithelium and cancer cells triggered downregulation of the progesterone receptor-B isoform and upregulation of the progesterone receptor-A isoform, resulting in an imbalance in the native ratio of progesterone receptor A and B isoforms [19].
• Glutathione S-transferase pull-down and coimmunoprecipitation assays demonstrated direct interaction of MTA1 with HIF-1alpha both in vitro and in vivo [20].
• Likewise, receptor tyrosine kinase signaling can also alter the expression of ER coregulators such as metastasis-associated antigen 1, leading to hormonal independence [21].

Physical interactions of MTA1

• Furthermore, MTA1 directly interacts with histone deacetylase-1 and -2 and with the activation domain of ER-alpha [1].
• We show that estrogen signaling promotes nuclear translocation of MAT1 and that MTA1 interacts with MAT1 both in vitro and in vivo [9].
• The data reported here demonstrate that endogenous c-MYC binds to the genomic MTA1 locus and recruits transcriptional coactivators [22].
• NRIF3 interacted with MTA1 both in vitro and in vivo [23].
• Metastasis-associated protein 1 (MTA1) is a component of the Mi-2/nucleosome remodeling and deacetylating complex and acts as a potent corepressor of estrogen receptor in breast cancer cells [24].

Regulatory relationships of MTA1

• Most importantly, short hairpin RNA (shRNA)-mediated knockdown of MTA1 blocks the ability of c-MYC to transform mammalian cells [22].
• The purpose of this study was to investigate the effects of a potent LHRH agonist, [D-Trp(6)]LHRH on the basal and EGF-induced cell proliferation and the metastasis-associated properties in A431 human epidermoid carcinoma [25].

Other interactions of MTA1

• Here we report the identification of metastatic-associated protein 1 (MTA1), a component of histone deacetylase (HDAC) and nucleosome-remodelling complexes, as a gene product induced by heregulin-beta1 (HRG) [1].
• We suggest that MTA1 associates with a different set of transcription factors from MTA2 and that this property may contribute to the metastatic potential of cells overexpressing MTA1 [13].
• We also report the finding of human MTA3, which is highly homologous to both MTA1 and MTA2 [13].
• Using a yeast two-hybrid screen with the MTA1 C-terminal domain as bait, we identified MAT1 (ménage á trois 1) as an MTA1-binding protein [9].
• Here, we explored the possibility of cross-talk between MTA1 and hypoxia-inducible factor-1alpha (HIF-1alpha), a key regulator of angiogenic factors [2].

Analytical, diagnostic and therapeutic context of MTA1

• The expression levels of MTA1 protein and the acetylation levels of histone H4 were examined in 70 cases of surgically resected esophageal squamous cell carcinomas, using immunohistochemistry [15].
• Using Southern blot analysis the MTA1 gene was highly conserved, and using Northern blot analysis MTA1 transcripts were found in virtually all human cell lines (melanoma, breast, cervix and ovarian carcinoma cells and normal breast epithelial cells) [8].
• Analyzing DNA microarray data, we found MTA1 to be selectively overexpressed in metastatic prostate cancer compared with clinically localized prostate cancer and benign prostate tissue [26].
• Paradoxically, for localized disease, higher MTA1 protein expression was associated with lower rates of prostate specific antigen recurrence after radical prostatectomy for localized disease [26].
• Western blot analysis of 6 tumor specimens showed increased expression of MTA1 in all the tumors analyzed [24].

References