Acetylation of androgen receptor by ARD1 promotes dissociation from HSP90 complex and prostate tumorigenesis
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John S. DePaolo1,2,*, Zehua Wang1,2,*, Jianhui Guo1,2,*, Guanyi Zhang3, Chiping Qian1,2, Haitao Zhang3, Jovanny Zabaleta2,4, Wanguo Liu1,2
1Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
2Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
3Department of Pathology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
4Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
*These authors contributed equally to this work
Wanguo Liu, email: [email protected]
Keywords: ARD1, AR acetylation, AR-HSP90 dissociation, prostate tumorigenesis
Received: April 13, 2016 Accepted: September 02, 2016 Published: September 21, 2016
Prostate cancer is an androgen receptor (AR)-driven disease and post-translational modification of AR is critical for AR activation. We previously reported that Arrest-defective protein 1 (ARD1) is an oncoprotein in prostate cancer. It acetylates and activates AR to promote prostate tumorigenesis. However, the ARD1-targeted residue within AR and the mechanisms of the acetylation event in prostate tumorigenesis remained unknown. In this study, we show that ARD1 acetylates AR at lysine 618 (K618) in vitro and in vivo. An AR construct with the charged lysine substitution by arginine (AR-618R) reduces RNA Pol II binding, AR transcriptional activity, prostate cancer cell growth, and xenograft tumor formation due to attenuation of AR nuclear translocation, whereas, construct mimicking neutral polar substitution acetylation at K618 by glutamine (AR-618Q) enhanced these effects beyond that of the wild-type AR. Mechanistically, ARD1 forms a ternary complex with AR and HSP90 in vitro and in vivo. 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 while the HSP90-dissociated AR is acetylated following ligand exposure. 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.
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