Role of Corepressor Complexes in an Androgen Receptor-Mediated Transcriptional Regulation

摘要

Recent studies have implicated N-CoR and SMRT in repression by antagonist-bound AR, and corepressors modulate the action of various antiandrogens in a different way. For example, it has been reported that SMRT binds to AR only after treatment with the progestagenic antiandrogen cyproterone acetate but not in the presence of nonsteroidal antagonists hydroxyflutamide or biculutamide. What is even more intriguing is the finding that both N-CoR and SMRT are negative regulators of agonist bound AR transcriptional activity. Consistent with this, our recent study confirmed that both N-CoR and SMRT were recruited to the endogeneous promoter region of the AR regulated gene, prostate-specific antigen (PSA), in the presence of either agonist or antagonists. Thus, corepressors SMRT and N-CoR may have important role in modulating both agonist- and antagonist-regulated function of AR. Understanding the mechanism responsible for transcriptional regulation by corepressor complexes will help to develop more effective antagonists for treating androgen-independent prostate cancer. We first selected a set of androgen-regulated genes and determine their promoter regions by RT-PCR and TRANSFAC database mining. Next, we confirmed the recruitment of corepressor N- CoR to the AREs of endgeneus AR-regulated genes, TSC22, NKX3-l and TMPRSS2 in the presence of agonist and antagonist. It suggests that N-CoR are generally involved in agonist-regulated transcription by AR.