p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation

The androgen receptor (AR) is a sequence-specific DNA-binding protein that plays a key role in prostate cancer cellular proliferation by dihydrotestos terone and the induction of secondary sexual characteristics. In this study me demonstrate that the AR can be modified by acetylation in vitro and in vivo, p300 and p300/cAMP-response element-binding protein acetylated the AR at a highly conserved lysine-rich motif carboxyl-terminal to the zinc fing er DNA-binding domain. [C-14]acetate-labeling experiments demonstrated that AR acetylation by p300 in cultured cells requires the same residues identi fied in vitro. Point mutation of the AR acetylation site (K632A/K633A) abro gated dihydrotestosterone-dependent transactivation of the AR in cultured c ells. Mutation of the p300 CH3 region or the p300/cAMP-response element-bin ding protein histone acetylase domain reduced ligand-dependent AR function. The identification of the AR as a direct target of histone acetyltransfera se co-activators has important implications for targeting inhibitors of AR function.