Differential requirement of SWI/SNF for androgen receptor activity.
The androgen receptor (AR) is a ligand-dependent transcription factor whose activity is required for prostate cancer proliferation. Because ablation of AR activity is a critical goal of prostate cancer therapy, much emphasis has been placed on understanding the accessory proteins that regulate AR function in the prostate. Several co-activators have been shown to be required for full AR activity, including histone acetyl-transferases and TRAP/mediator complexes. SWI/SNF comprises a family of large, multisubunit complexes present in the cell, which contain one of two core ATPases required for nucleosome re-positioning, BRG1 or hBRM. We investigated the specific requirement of the SWI/SNF core ATPases for AR function. Using cells deficient in both BRG1 and hBRM, we show that activation of one AR target promoter, prostate-specific antigen (PSA), requires SWI/SNF chromatin remodeling for activity. A second AR target promoter, probasin, maintained a low level of activation in the absence of SWI/SNF. AR stimulation on the probasin core promoter could be partially induced with BRG1, but hBRM strongly stimulated AR activity. The PSA promoter was only induced by the restoration of hBRM. In contrast, ligand-dependent activation of the estrogen receptor was equally stimulated by BRG1 or hBRM. We demonstrate that the addition of a known enhancer region to the core PSA promoter bypasses the requirement for SWI/SNF on the PSA promoter, indicating that elements upstream of specific proximal promoters can impact the influence of the SWI/SNF complex on target gene activation. Addition of the enhancer to the probasin core promoter failed to impact the SWI/SNF requirement. In summary, SWI/SNF function potently regulates core AR target gene promoter activation, with a preference for hBRM-containing complexes. These studies highlight a role for the enhancer in altering the impact of SWI/SNF action and suggest a disparity in AR target genes for SWI/SNF requirement.
Marshall
Thomas W
TW
Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521, USA.
Link
Kevin A
KA
Petre-Draviam
Christin E
CE
Knudsen
Karen E
KE
D000727:Androgen-Binding Protein / Q000235:genetics; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism*; D004265:DNA Helicases; D004742:Enhancer Elements, Genetic / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D000727:Androgen-Binding Protein; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; D011944:Receptors, Androgen; C084011:SMARCA2 protein, human; D014157:Transcription Factors; C027519:probasin; D017430:Prostate-Specific Antigen; C084108:SMARCA4 protein, human; D004265:DNA Helicases