Positive feedback loop mediated by protein phosphatase 1α mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer.

Abstract

P-TEFb (CDK9/cyclin T) plays a central role in androgen receptor (AR)-mediated transactivation by phosphorylating both RNA polymerase 2 complex proteins and AR at S81. CDK9 dephosphorylation mobilizes P-TEFb from an inhibitory 7SK ribonucleoprotein complex, but mechanisms targeting phosphatases to P-TEFb are unclear. We show that AR recruits protein phosphatase 1α (PP1α), resulting in P-TEFb mobilization and CDK9-mediated AR S81 phosphorylation. This increased pS81 enhances p300 recruitment, histone acetylation, BRD4 binding and subsequent further recruitment of P-TEFb, generating a positive feedback loop that sustains transcription. AR S81 is also phosphorylated by CDK1, and blocking basal CDK1-mediated S81 phosphorylation markedly suppresses AR activity and initiation of this positive feedback loop. Finally, androgen-independent AR activity in castration-resistant prostate cancer (CRPC) cells is driven by increased CDK1-mediated S81 phosphorylation. Collectively these findings reveal a mechanism involving PP1α, CDK9 and CDK1 that is used by AR to initiate and sustain P-TEFb activity, which may be exploited to drive AR in CRPC.

• Authors: Xiaming Liu, Yanfei Gao, HuiHui Ye, Sean Gerrin, Fen Ma, Yiming Wu, Tengfei Zhang, Joshua Russo, Changmeng Cai, Xin Yuan, Jihong Liu, Shaoyong Chen, Steven P Balk
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 45 Issue 7 Pg. 3738-3751 (04 20 2017) ISSN: 1362-4962 [Electronic] England
• PMID: 28062857 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• Androgen Receptor Antagonists
• Chromatin
• Receptors, Androgen
• Positive Transcriptional Elongation Factor B
• CDC2 Protein Kinase
• Cyclin-Dependent Kinase 9
• Protein Phosphatase 1

Topics

• Androgen Receptor Antagonists (pharmacology)
• CDC2 Protein Kinase (metabolism)
• Cell Line, Tumor
• Chromatin (metabolism)
• Cyclin-Dependent Kinase 9 (metabolism)
• Feedback, Physiological
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Positive Transcriptional Elongation Factor B (metabolism)
• Prostatic Neoplasms (enzymology, genetics, metabolism)
• Protein Phosphatase 1 (metabolism)
• Receptors, Androgen (metabolism)
• Transcriptional Activation