Targeting the BAF57 SWI/SNF Subunit in Prostate Cancer: A Novel Platform to Control Androgen Receptor Activity

Abstract

The androgen receptor (AR) is critical for disseminated prostate cancer proliferation and survival. AR activity is targeted either through prevention of ligand synthesis or through the use of antagonists that bind the COOH-terminal ligandbinding domain. Although initially effective, treatment fails due to restored AR activity in the presence of therapeutics. Thus, new means must be developed to target AR activity. The SWI/SNF chromatin remodeling complex is critical for AR transcriptional activity, and the BAF57 SWI/SNF subunit facilitates direct interaction with the receptor. Although selected SWI/SNF subunit expression is reduced in prostate cancer, we show that BAF57 is retained in human disease and is elevated in a subset of tumors. Functional analyses showed that BAF57 contributes uniquely to androgen-mediated stimulation of transcription without compromising the effectiveness of AR antagonists. Subsequent studies revealed that BAF57 is recruited to the AR DNA-binding domain/hinge region, which occurs concomitant with receptor activation. These data provided the basis for a novel inhibitor derived from BAF57 [BAF57 inhibitory peptide (BIPep)], which blocked AR residence on chromatin and resultant AR-dependent gene activation. Importantly, BIPep expression was sufficient to inhibit androgen-dependent prostate cancer cell proliferation in AR-positive cells. In summary, these data identify blockade of AR-BAF57 interaction as a novel means to target agonistinduced AR function in prostate cancer, and provide the first evidence that abrogation of SWI/SNF function can be developed as a point of therapeutic intervention in prostate cancer. [Cancer Res 2008;68(12):4551-8]

Regulation of Androgen Receptor-dependent Transcription by Coactivator MED1 Is Mediated through a Newly Discovered Noncanonical Binding Motif

“…One interpretation of these findings is that the ligand-induced AR N/C interaction results in a conformational change that renders the Tau-1 domain accessible for MED1 binding. Notably, the N/C interaction was also shown to be required for AR binding with the SWI/SNF chromatin remodeling complex (49), although in this case, the primary AR recruitment surface appears to be located within the hinge region (18). Another possible explanation for the N/C interaction requirement for MED1-AR binding may be that MED1 contacts additional surfaces on the C terminus of AR that in turn may serve to stabilize the MED1-Tau-1 interaction.…”

“…For example, members of the p160/SRC family of coactivators directly bind to the Tau-5 domain of the AR NTD via conserved Gln-rich regions in a manner that is independent of their intrinsic LXXLL motifs (14 -16). Coactivator complexes shown to interact with the AR hinge region include the BAF57-containing SWI/SNF complex and the p300/PCAF complex (17,18). Interestingly, mutational analyses of the AR NTD have also implicated the Tau-1 domain as a potential coactivator binding surface (19), yet the identity of the corresponding interacting coregulatory factors remain unclear.…”

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

“…RNA was isolated and cDNA generated as previously described (52). Q-PCR was performed with an ABI Step-One apparatus using Power SYBR Green Master Mix and primers described in Supplemental Table 2.…”

“…Cells were cultured in steroid-free (CDT) media for 72 hours and stimulated with 0.1% EtOH, 10 nM DHT, or 10 μM Bic as indicated. ChIP analyses and PCR were performed as previously described (52,53). Quantification of the recovered DNA products was also determined by qPCR.…”

Hic-5 is a transcription coregulator that acts before and/or after glucocorticoid receptor genome occupancy in a gene-selective manner

“…Hinge regions of other nuclear receptors are also important for transcriptional activation (15)(16)(17). Only a few coregulators that interact with the hinge region of nuclear receptors have been identified, including HEXIM1, JDP2, TAFII30, SNURF, ASC-1, BAF57, and hydrogen peroxide-inducible clone-5 (Hic-5, TGFB1I1) (18)(19)(20)(21)(22)(23)(24). Hic-5 is the only protein known to bind the relatively uncharacterized GR tau2 (24).…”