Differential Requirement of SWI/SNF for Androgen Receptor Activity

Abstract

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 acetyltransferases 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.

The SWI/SNF complex and cancer

“…The oncogenic transcription heterodimer activated protein-1 (AP-1) is known to be SWI/SNF dependent ; similarly, EKLF, which regulates b-hemogloblin synthesis, also requires this complex for its function (Armstrong et al, 1998;Lee et al, 1999). All known steroid receptors are functionally linked to SWI/SNF (Yoshinaga et al, 1992;Sumi-Ichinose et al, 1997;Fryer and Archer, 1998;Belandia et al, 2002;Inoue et al, 2002;Marshall et al, 2003;Flajollet et al, 2007). SWI/SNF has been linked to CD44, CEACAM1, E-cadherin and various integrins (Liu et al, 2001;Hendricks et al, 2004;Hill et al, 2004).…”

“…Although it has not been investigated, the loss of BRG1 and BRM could very well underlie the resistance to glucocorticoids in hematopoietic malignancies such as myeloma, lymphoma and leukemia, as well as in lung cancer (Choi et al, 2001b;Ko et al, 2004;Pottier et al, 2007). The estrogen receptor is also functionally linked to the SWI/SNF complex Belandia et al, 2002), and the androgen receptor is also SWI/SNF dependent (Inoue et al, 2002;Marshall et al, 2003;Hong et al, 2005;Link et al, 2005;Dai et al, 2008). We have found that BRG1 and BRM are lost in human prostate cancer samples, suggesting that a loss of SWI/SNF function may play a role in the development of hormone-refractory prostate cancer.…”

Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation

“…4A). To analyze a larger spectrum of validated AR targets, cyclin D1b-mediated regulation of probasin (ARR2) and sex-limited protein (SLP) expression was assessed (33,34). As shown, SLP-HRE2-LUC inhibition was compromised in a manner comparable with the PSA promoter, resulting in a 2.2-fold increase in AR activity as compared with cyclin D1a (Fig.…”

“…3 C and D). Identical conditions were used to assess cyclin D1b impact on the PSA-LUC reporter, which lacks the distal enhancer region and associated AREs (33). Again, cyclin D1b failed to repress AR activity to the capacity of cyclin D1a (Fig.…”

Novel Mechanism of Negative Regulation of 1,25-Dihydroxyvitamin D3-induced 25-Hydroxyvitamin D3 24-Hydroxylase (Cyp24a1) Transcription

“…BRG1 was also shown to be required for androgen receptor activation of mouse mammary tumor virus transcription (39). However, Brm-containing complexes have been reported to be preferred in androgen receptor-mediated transcriptional activation of prostate-specific antigen and probasin (40). In the absence of SWI/SNF activity, androgen receptor-dependent activation of prostate-specific antigen transcription could not be restored by BRG1 but was strongly activated by Brm (40).…”