Abstract
The transcriptional activity of estrogen receptor-alpha is controlled by coregulators. 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. 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. MAT1 is an assembly/targeting factor for cyclin-dependent kinase-activating kinase (CAK), which has been shown to functionally interact with general transcriptional factor TFIIH, a known inducer of ER transactivation. We show that estrogen signaling promotes nuclear translocation of MAT1 and that MTA1 interacts with MAT1 both in vitro and in vivo. MAT1 binds to the C-terminal 389-441 amino acids GATA domain and N-terminal 1-164 amino acids bromo-domain of MTA1, whereas MTA1 binds to the N-terminal ring finger domain of the MAT1. In addition, MAT1 interacts with the activation function 2 domain of ER and colocalizes with ER in activated cells. MTA1 deregulation in breast cancer cells led to its interactions with the CAK complex components, ER, and HDAC2. Accordingly, MTA1 inhibited CAK stimulation of ER transactivation that was partially relieved by HDAC inhibitor trichostatin A, suggesting that MTA1 might inhibit CAK-induced transactivation function of ER by recruiting HDAC. Furthermore, MTA1 overexpression inhibited the ability of CAK complex to phosphorylate ER. Together, these findings identified MAT1 as a target of MTA1 and provided new evidence to suggest that the transactivation functions of ER might be influenced by the regulatory interactions between CAK and MTA1 in breast cancer cells.
Highlights
The eukaryotic genome is compacted with histone and other proteins to form chromatin, which consists of repeating units of nucleosome [1, 2]
We show that estrogen signaling promotes nuclear translocation of MAT1 and that MTA1 interacts with MAT1 both in vitro and in vivo
We show that MTA1 interacts with MAT1 both in vitro and in vivo and that MTA1 could be detected in a complex consisting of cyclin-dependent kinase-activating kinase (CAK) components estrogen receptor-␣ (ER) and histone deacetylases (HDACs) in breast cancer cells
Summary
The eukaryotic genome is compacted with histone and other proteins to form chromatin, which consists of repeating units of nucleosome [1, 2]. Formation of nucleosomes and higher order chromatin structures can render the DNA inaccessible to transcription factors and complexes. For transcription factors to access DNA, the repressive chromatin structure needs to be. Dynamic alterations in the chromatin structure can facilitate or suppress the access of the transcription factors to nucleosomal DNA, leading to transcriptional regulation. Because HDACmediated deacetylation of nucleosomal histones is known to be associated with transcriptional repression of some genes, it is being proposed that the deregulation of recruitment of HDACcontaining repressor complex to specific target promoters could serve as a potential mechanism by which these enzymes contribute to tumorigenesis. MTA1 (metastasis-associated protein 1) represses estrogen receptor-␣ (ER)-driven transcription by recruiting HDAC to the ER response element (ERE)-containing target gene chromatin in breast cancer cells [7]. The RING finger domain is linked with general transcription factor TFIIH-mediated transcription [17], the coiled-coil domain in making contact with TFIIH via XPB and XPD helicase sub-
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