BAF57 Governs Androgen Receptor Action and Androgen-Dependent Proliferation through SWI/SNF

Abstract

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.

ACKNOWLEDGMENTS

We thank Weidong Wang for the generous gift of the BAF57 antibodies. We thank Erik Knudsen, Christin Petre, Chris Mayhew, Hasan Siddiqui, and Janet Hess-Wilson for critical reading of the manuscript. We thank Robert Matusik, Tom Case, Simon Hayward, and Janni Mirosevich for training in prostate tissue microdissection and immunohistochemistry.

This study was supported by DAMD 02-1-0037 (K.E.K.) and RO1CA099996 (K.E.K.). B.W., G.R., and E.H. are supported by grants CA91048 and CA102848. K.A.L. is supported by NIEHS training grant 2 T32 ES07250-16.