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Androgen ablation elicits PP1‐dependence for AR stabilization and transactivation in prostate cancer
Author(s) -
Liu Xiaming,
Han Weiwei,
Gulla Sarah,
Simon Nicholas I.,
Gao Yanfei,
Liu Jihong,
Wang Liang,
Yang Hongmei,
Zhang Xiaoping,
Chen Shaoyong
Publication year - 2016
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23157
Subject(s) - lncap , androgen receptor , prostate cancer , transactivation , androgen , cancer research , endocrinology , biology , protein degradation , medicine , cancer , microbiology and biotechnology , transcription factor , hormone , biochemistry , gene
BACKGROUND Previous reports have documented protein phosphatase 1 (PP1) as an essential androgen receptor (AR) activator. However, more systemic studies are needed to further define PP1 effects on AR, particularly in the settings of prostate cancer cells and under conditions mimicking androgen ablation. METHODS PP1 effects on AR protein expression, degradation, ubiquitination, and stabilization were examined in non‐prostate cancer cells, followed by validation on exogenous settings in androgen‐sensitive (LNCaP and VCaP) and castration‐resistant (C4‐2) prostate cancer cells. Effects of PP1 on AR protein expression, on AR‐mediated transcription of exogenous reporter and endogenous gene, and on LNCaP and C4‐2 cell proliferation were monitored under androgen‐containing versus androgen‐depleted conditions to assess the effects of PP1 on AR responsiveness to androgen. RESULTS In this report, we determined that PP1 functions to stabilize AR proteins that exclusively undergo the proteasome‐dependent degradation, and the stimulatory effects of PP1 were predominantly mediated by the AR ligand‐binding domain (LBD). Consistently, PP1 enhances AR protein stability by disrupting the LBD‐mediated and K48‐linked ubiquitination cascade. We further validated the above findings in the prostate cancer cells by showing that PP1 inhibition can increase ubiquitin‐ and proteasome‐dependent degradation of endogenous AR under androgen deprivation. Significantly, we found that PP1 could markedly activate AR transcriptional activities under conditions mimicking androgen ablation and that androgen sensitivity was substantially evoked by PP1 inhibition in the prostate cancer cell lines. CONCLUSIONS As summarized in a simplified model, our studies defined an essential PP1‐mediated pathway for AR protein stabilization that can compensate the loss of androgen and established a mechanistic link between PP1 and androgen responsiveness. The amplified PP1‐dependence for AR activation under the androgen ablated conditions provides a rationale to therapeutically target the PP1‐AR module in the castration–resistant prostate cancer (CRPC). Our findings also suggested an alternative AR‐targeting compounds screening strategy that aims to circumvent PP1‐AR interaction. Prostate 76:649–661, 2016 . © 2016 Wiley Periodicals, Inc.