title: Androgen ablation elicits PP1-dependence for AR stabilization and transactivation in prostate cancer.
abstract: 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.
authors: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.|Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors: Xiaming
authors: X
authors: Liu
authors: Department of Urology, Union Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, China.
authors: Weiwei
authors: W
authors: Han
authors: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors: Sarah
authors: S
authors: Gulla
authors: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors: Nicholas I
authors: NI
authors: Simon
authors: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors: Yanfei
authors: Y
authors: Gao
authors: Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors: Jihong
authors: J
authors: Liu
authors: Department of Radiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors: Liang
authors: L
authors: Wang
authors: Department of Pathogen Biology, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, China.
authors: Hongmei
authors: H
authors: Yang
authors: Department of Urology, Union Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, China.
authors: Xiaoping
authors: X
authors: Zhang
authors: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors: Shaoyong
authors: S
authors: Chen
mesh_terms: D000728:Androgens / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D054645:Protein Phosphatase 1
keywords: androgen ablation; androgen receptor; prostate cancer; protein degradation; protein phosphatase 1; transactivation