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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

Department of Biochemistry and Molecular Biology (H.-G.Y.), Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul 120-752, South Korea; and Department of Molecular and Cellular Biology (J.W.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Jiemin Wong, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: jwong{at}bcm.tmc.edu.

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(ß-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.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   p300  |  SRC-1  |  AIB1  |  NCOR  |  SMRT

Ligands:   Bicalutamide  |  R1881

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