The corepressors silencing mediator of retinoid and thyroid hormone receptor and nuclear receptor corepressor are involved in agonist- and antagonist-regulated transcription by androgen receptor.
We have investigated the role of corepressors SMRT (silencing mediator of retinoid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) in transcriptional regulation by androgen receptor (AR) in the LNCaP prostate cancer cell line. Using specific small interference RNAs to knock down SMRT and/or N-CoR in LNCaP cells, we found that SMRT and N-CoR not only mediate antagonist-dependent inhibition of AR activation but also have a widespread role in suppressing agonist-dependent activation of several AR target genes we have tested, including PSA (prostate-specific antigen), TSC22 (TSC22 domain family member 1), NKX3-1 (NK3 transcription factor locus 1), and B2M(beta-2-microglobulin). By sequencing analysis followed by analysis of physical association by chromatin immunoprecipitation assay, we mapped the putative androgen response elements in the NKX3-1 and B2M. Consistent with a role in both antagonist- and agonist-regulated transcription by AR, chromatin immunoprecipitation analysis revealed that both SMRT and N-CoR were recruited by AR to these genes in the presence of either flutamide or R1881. Knocking down SMRT and N-CoR enhanced the recruitment of the coactivators steroid receptor coactivator 1 and p300 by agonist-bound AR and led to increased hyperacetylation of histone H3 and H4, suggesting that the corepressors actively compete with coactivators for binding to agonist-bound AR. Taken together, our data indicate that SMRT and N-CoR corepressors are involved in transcriptional regulation by both agonist- and antagonist-bound AR and regulate the magnitude of hormone response, at least in part, by competing with coactivators.
Yoon
Ho-Geun
HG
Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul, South Korea.
Wong
Jiemin
J
D000107:Acetylation; D059002:Androgen Receptor Antagonists; D000728:Androgens; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D001613:beta 2-Microglobulin / Q000235:genetics
D059002:Androgen Receptor Antagonists; D000728:Androgens; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; C491178:NKX3-1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D012097:Repressor Proteins; C099726:TSC22D1 protein, human; D014157:Transcription Factors; D001613:beta 2-Microglobulin; D017430:Prostate-Specific Antigen