Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation

// Xiaming Liu 1, * , Weiwei Han 2, * , Sarah Gulla 1 , Nicholas I. Simon 1 , Yanfei Gao 1 , Changmeng Cai 1 , Hongmei Yang 3 , Xiaoping Zhang 2 , Jihong Liu 4 , Steven P. Balk 1 , Shaoyong Chen 1 1 Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA 2 Department of Urology, Union Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan 430022, China 3 Department of Pathogen Biology, Tongji Medical School, Huazhong University of Science and Technology, Wuhan 430030, China 4 Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China * These authors have contributed equally to this work Correspondence to: Shaoyong Chen, e-mail: schen@bidmc.harvard.edu Steven P. Balk, e-mail: sbalk@bidmc.harvard.edu Keywords: androgen receptor, prostate cancer, protein phosphatase 1 Received: August 06, 2015      Accepted: November 18, 2015      Published: November 30, 2015 ABSTRACT The phosphoprotein phosphatases are emerging as important androgen receptor (AR) regulators in prostate cancer (PCa). We reported previously that the protein phosphatase 1 catalytic subunit (PP1α) can enhance AR activity by dephosphorylating a site in the AR hinge region (Ser650) and thereby decrease AR nuclear export. In this study we show that PP1α increases the expression of wildtype as well as an S650A mutant AR, indicating that it is acting through one or more additional mechanisms. We next show that PP1α binds primarily to the AR ligand binding domain and decreases its ubiquitylation and degradation. Moreover, we find that the PP1α inhibitor tautomycin increases phosphorylation of AR ubiquitin ligases including SKP2 and MDM2 at sites that enhance their activity, providing a mechanism by which PP1α may suppress AR degradation. Significantly, the tautomycin mediated decrease in AR expression was most pronounced at low androgen levels or in the presence of the AR antagonist enzalutamide. Consistent with this finding, the sensitivity of LNCaP and C4–2 PCa cells to tautomycin, as assessed by PSA synthesis and proliferation, was enhanced at low androgen levels or by treatment with enzalutamide. Together these results indicate that PP1α may contribute to stabilizing AR protein after androgen deprivation therapies, and that targeting PP1α or the AR-PP1α interaction may be effective in castration-resistant prostate cancer (CRPC).