Carcinogenesis Advance Access originally published online on May 16, 2008
Carcinogenesis 2008 29(9):1725-1733; doi:10.1093/carcin/bgn117
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Published by Oxford University Press 2008.
Prohibitin and the SWI/SNF ATPase subunit BRG1 are required for effective androgen antagonist-mediated transcriptional repression of androgen receptor-regulated genes
Department of Medicine, Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, USA
* To whom correspondence should be addressed. Tel: +1 617 638 5650; Fax: +1 617 638 5609; Email: yandai{at}bu.edu
Correspondence may also be addressed to Douglas V.Faller. Tel: +1 617 638 4173; Fax: +1 617 638 4176; Email: dfaller{at}bu.edu
Androgen antagonists or androgen deprivation are the primary therapeutic modalities for the treatment of prostate cancer. Invariably, however, the disease becomes progressive and unresponsive to androgen ablation therapy (hormone refractory). The molecular mechanisms by which androgen antagonists inhibit prostate cancer proliferation are not fully defined. In this study, we identify two molecules which are required for effective prostate cancer cell responsiveness to androgen antagonists. We establish that androgen receptor (AR)-dependent transcriptional suppression by androgen antagonists requires the tumor suppressor prohibitin. This requirement for prohibitin was demonstrated using structurally-distinct androgen antagonists, stable and transient knockdown of prohibitin and transfected and endogenous AR-responsive genes. The SWI–SNF complex core ATPase BRG1, but not its closely-related counterpart ATPase BRM, is required for this repressive action of prohibitin on AR-responsive promoters. Androgen antagonists induce recruitment of prohibitin and BRG1 to endogenous AR-responsive promoters and induce a physical association between AR and prohibitin and BRG1. The recruitment of prohibitin to endogenous AR-responsive promoters is dependent upon antagonist-bound AR. Prohibitin binding in the prostate-specific antigen (PSA) promoter results in the recruitment of BRG1 and the dissociation of p300 from the PSA promoter. These findings suggest that prohibitin may function through BRG1-mediated local chromatin remodeling activity and the removal of p300-mediated acetylation to produce androgen antagonist-mediated transcriptional repression. Furthermore, in addition to its necessary role in AR-mediated transcriptional repression, we demonstrate that prohibitin is required for full and efficient androgen antagonist-mediated growth suppression of prostate cancer cells.
Abbreviations: AR, androgen receptor; ChIP, chromatin immunoprecipitation; DHT, dihydrotestosterone; ER, estrogen receptor; FBS, fetal bovine serum; HDAC, histone deacetylase; mRNA, messenger RNA; NCoR, nuclear corepressor; PCR, polymerase chain reaction; PSA, prostate-specific antigen; PSA-LUC, prostate-specific antigen promoter-driven luciferase reporter; SiRNA, short-inhibitory RNA
Received August 25, 2007; revised March 23, 2008; accepted May 6, 2008.
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