Oncotarget

Research Papers:

Differential regulation of the androgen receptor by protein phosphatase regulatory subunits

James Grey _, Dominic Jones, Laura Wilson, Sirintra Nakjang, Jake Clayton, Richard Temperley, Emma Clark, Luke Gaughan and Craig Robson

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Oncotarget. 2018; 9:3922-3935. https://doi.org/10.18632/oncotarget.22883

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Abstract

James Grey1, Dominic Jones1, Laura Wilson1, Sirintra Nakjang1, Jake Clayton1, Richard Temperley1, Emma Clark1, Luke Gaughan1 and Craig Robson1

1Northern Institute for Cancer Research, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

Correspondence to:

James Grey, email: [email protected]

Keywords: androgen receptor; prostate cancer; castrate resistant prostate cancer; phosphatase; myosin phosphatase

Received: November 01, 2017     Accepted: November 09, 2017     Published: December 04, 2017

ABSTRACT

The Androgen Receptor (AR) is a key molecule in the development, maintenance and progression of prostate cancer (PC). However, the relationship between the AR and co-regulatory proteins that facilitate AR activity in castrate resistant settings remain understudied. Here we show that protein phosphatase 1 regulatory subunits, identified from a phosphatase RNAi screen, direct PP1 catalytic subunits to a varied yet significant response in AR function. As such, we have characterised the PP1β holoenzyme, myosin phosphatase (MLCP), as a novel ligand independent regulator of the AR. Sustained MLCP activity through down-regulation of the MLCP inhibitory subunit, PPP1R14C, results in impaired AR nuclear translocation, protein stability and transcriptional activity in distinct models of PC progression, culminating in restoration of a non-malignant prostate genotype. Phenotypically, a marked reduction in cell proliferation and migration, characterised by G1 cell cycle arrest is observed, confirming PP1 holoenzyme disruption as a novel treatment approach in PC.


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