title: Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation.
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).
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Xiaming
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Han
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gulla
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Simon
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
authors.affiliation: Department of Pathogen Biology, Tongji Medical School, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Chen
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001549:Benzamides; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009154:Mutation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013141:Spiro Compounds / Q000494:pharmacology; D054875:Ubiquitination
chemical_list: D001549:Benzamides; D009570:Nitriles; D011714:Pyrans; D011944:Receptors, Androgen; D013141:Spiro Compounds; C053079:tautomycin; D010669:Phenylthiohydantoin; C540278:enzalutamide; D051736:Proto-Oncogene Proteins c-mdm2; D054645:Protein Phosphatase 1; D017430:Prostate-Specific Antigen
keywords: androgen receptor; prostate cancer; protein phosphatase 1