BAF57 governs androgen receptor action and androgen-dependent proliferation through SWI/SNF.
Androgen receptor (AR) activity is required for prostate cancer development and progression. Thus, there is a major impetus to understand the regulation of AR action. We and others have previously shown that AR transactivation potential is dependent on the presence of an active SWI/SNF chromatin remodeling complex. However, the mechanisms underlying SWI/SNF regulation of the AR remained unsolved. We show here that the BAF57 subunit, an accessory component of the remodeling complex, is a critical regulator of AR function. We show that BAF57 is expressed in the luminal epithelia of the prostate and is required for AR-dependent transactivation in prostatic adenocarcinoma cells. Our data reveal that BAF57 can directly bind to the AR and is recruited to endogenous AR targets upon ligand activation. Loss of BAF57 or inhibition of BAF57 function severely compromised AR activity, as observed with both exogenous and endogenous AR targets. Rescue of BAF57 function restored AR activity, thus demonstrating a specific requirement of BAF57 for AR activity. This action of BAF57 proved to be dependent on SWI/SNF ATPase function. BAF57 has previously been implicated in nuclear receptor coactivator function, and we show that, although BAF57 facilitated coactivator activity, only a selected subset required BAF57 for coactivator function. Lastly, we demonstrate that both BAF57 and BRM are required for the proliferation of AR-dependent prostatic adenocarcinoma cells. In summary, these findings identify BAF57 as a critical modulator of the AR that is capable of altering AR activity, coactivator function, and AR-dependent proliferation.
Link
Kevin A
KA
Department of Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
Burd
Craig J
CJ
Williams
Erin
E
Marshall
Thomas
T
Rosson
Gary
G
Henry
Erin
E
Weissman
Bernard
B
Knudsen
Karen E
KE
D000230:Adenocarcinoma / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins; D004848:Epithelium / Q000378:metabolism; D020868:Gene Silencing; D008024:Ligands; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D008024:Ligands; C110421:Mybbp1a protein, mouse; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen; C499503:Smarca2 protein, mouse; C465207:Smarce1 protein, mouse; D014157:Transcription Factors; D000251:Adenosine Triphosphatases
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