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The novel anti-androgen candidate galeterone targets deubiquitinating enzymes, USP12 and USP46, to control prostate cancer growth and survival

Lookup NU author(s): Dr Urszula McClurg, Dr Mahsa AzizyanORCiD, Dr Sirintra Nakjang, Professor Craig Robson

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

Abstract

Metastatic castration resistant prostate cancer is one of the main causes of male cancer associated deaths worldwide. Development of resistance is inevitable in patients treated with anti-androgen therapies. This highlights a need for novel therapeutic strategies that would be aimed upstream of the androgen receptor (AR). Here we report that the novel small molecule anti-androgen, galeterone targets USP12 and USP46, two highly homologous deubiquitinating enzymes that control the AR-AKT-MDM2-P53 signalling pathway. Consequently, galeterone is effective in multiple models of prostate cancer including both castrate resistant and AR-negative prostate cancer. However, we have observed that USP12 and USP46 selectively regulate full length AR protein but not the AR variants. This is the first report of deubiquitinating enzyme targeting as a strategy in prostate cancer treatment which we show to be effective in multiple, currently incurable models of this disease.

Publication metadata

Author(s): McClurg UL, Azizyan M, Dransfield DT, Namdev N, Chit NCTH, Nakjang S, Robson CN

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2018

Volume: 9

Issue: 38

Pages: 24992-25007

Print publication date: 18/05/2018

Online publication date: 18/05/2018

Acceptance date: 10/02/2018

Date deposited: 21/05/2018

ISSN (electronic): 1949-2553

Publisher: Impact Journals LLC

URL: https://doi.org/10.18632/oncotarget.25167

DOI: 10.18632/oncotarget.25167

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