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Lookup NU author(s): James Grey, Dr Dominic Jones, Laura WilsonORCiD, Dr Sirintra Nakjang, Jake Clayton, Dr Richard Temperley, Dr Emma ClarkORCiD, Dr Luke GaughanORCiD, Professor Craig Robson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© Grey et al. 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 PP1ß 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.
Author(s): Grey J, Jones D, Wilson L, Nakjang S, Clayton J, Temperley R, Clark E, Gaughan L, Robson C
Publication type: Article
Publication status: Published
Journal: Oncotarget
Year: 2018
Volume: 9
Issue: 3
Pages: 3922-3935
Online publication date: 04/12/2017
Acceptance date: 09/11/2017
Date deposited: 22/01/2018
ISSN (electronic): 1949-2553
Publisher: Impact Journals LLC
URL: https://doi.org/10.18632/oncotarget.22883
DOI: 10.18632/oncotarget.22883
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