Abstract 4598: Androgen receptor acetylation at K618 by ARD1 is essential for dissociation from HSP90 in prostate tumorigenesis

Abstract

Abstract Prostate cancer is an androgen receptor (AR)-driven disease and post-translational modification of AR is critical for its activation in both hormone-sensitive and castration-resistant disease. We previously reported that ARD1 is an oncoprotein in prostate cancer. It acetylates and activates AR to promote prostate tumorigenesis. However, the target residue within AR and the roles and mechanisms of the acetylation event in prostate tumorigenesis remained unknown. Here we show that ARD1 interacts with the AR DNA-binding domain and acetylates AR at lysine 618 (K618) in vivo and in vitro. Inhibition of K618 acetylation by replacing lysine with arginine significantly reduces AR transcriptional activity, prostate cancer cell growth, and xenograft tumor formation due to attenuation of AR nuclear translocation. Constitutive acetylation at K618 by replacing lysine with glutamine reverses these effects. Mechanistically, ARD1 forms a complex with both AR and HSP90. Expression of ARD1 increases levels of AR acetylation and AR-HSP90 dissociation in a dose dependent manner. Moreover, the AR acetylation-defective K618R mutant is unable to dissociate from HSP90 following ligand exposure, and HSP90-dissociated AR is acetylated. This work identifies a new mechanism for ligand-induced AR-HSP90 dissociation and AR activation. Targeting ARD1-mediated AR acetylation may be a potent intervention for AR-dependent prostate cancer therapy. Given that K618 is also present in AR variants, the significance of ARD1-dependent acetylation of AR variants for castration-resistant PCa will be discussed. Citation Format: John S. DePaolo, Zehua Wang, Jianhui Guo, Guanyi Zhang, Haitao Zhang, Jovanny Zabaleta, Wanguo Liu. Androgen receptor acetylation at K618 by ARD1 is essential for dissociation from HSP90 in prostate tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4598.