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



Burska, Urszula L, Harle, Victoria J, Coffey, Kelly, Darby, Steven, Ramsey, Hollie, O'Neill, Daniel, Logan, Ian R, Gaughan, Luke and Robson, Craig N
(2013) Deubiquitinating Enzyme Usp12 Is a Novel Co-activator of the Androgen Receptor. JOURNAL OF BIOLOGICAL CHEMISTRY, 288 (45). pp. 32641-32650.

[thumbnail of J. Biol. Chem.-2013-Burska-32641-50.pdf] Text
J. Biol. Chem.-2013-Burska-32641-50.pdf - Published version

Download (2MB)

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.

Item Type: Article
Uncontrolled Keywords: Androgen, Androgen Receptor, Chromatin Immunoprecipitation (ChIP), Deubiquitination, Prostate Cancer, uaf-1, usp12, wdr20
Depositing User: Symplectic Admin
Date Deposited: 18 Feb 2019 11:32
Last Modified: 19 Jan 2023 01:03
DOI: 10.1074/jbc.M113.485912
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3032827