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Deubiquitinating Enzyme Usp12 Is a Novel Co-activator of the Androgen Receptor

Lookup NU author(s): Dr Urszula McClurg, Victoria Harle, Dr Kelly Coffey, Dr Steven Darby, Hollie Ramsey, Daniel O'Neill, Dr Ian Logan, Dr Luke Gaughan, Professor Craig Robson

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

The androgen receptor (AR), a member of the nuclear receptor family, is a transcription factor involved in prostate cell growth, homeostasis, and transformation. AR is a key protein in growth and development of both normal and malignant prostate, making it a common therapeutic target in prostate cancer. AR is regulated by an interplay of multiple post-translational modifications including ubiquitination. We and others have shown that the AR is ubiquitinated by a number of E3 ubiquitin ligases, including MDM2, CHIP, and NEDD4, which can result in its proteosomal degradation or enhanced transcriptional activity. As ubiquitination of AR causes a change in AR activity or stability and impacts both survival and growth of prostate cancer cells, deubiquitination of these sites has an equally important role. Hence, deubiquitinating enzymes could offer novel therapeutic targets. We performed an siRNA screen to identify deubiquitinating enzymes that regulate AR; in that screen ubiquitin-specific protease 12 (Usp12) was identified as a novel positive regulator of AR. Usp12 is a poorly characterized protein with few known functions and requires the interaction with two cofactors, Uaf-1 and WDR20, for its enzymatic activity. In this report we demonstrate that Usp12, in complex with Uaf-1 and WDR20, deubiquitinates the AR to enhance receptor stability and transcriptional activity. Our data show that Usp12 acts in a pro-proliferative manner by stabilizing AR and enhancing its cellular function.


Publication metadata

Author(s): Ramsey H; Coffey K; Robson CN; Logan IR; Gaughan L; Darby S; Harle VJ; Burska UL; O'Neill D

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2013

Volume: 288

Issue: 45

Pages: 32641-32650

Print publication date: 08/11/2013

Online publication date: 21/09/2013

Date deposited: 16/10/2015

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology

URL: http://dx.doi.org/10.1074/jbc.M113.485912

DOI: 10.1074/jbc.M113.485912


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