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Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12

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

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Abstract

The TP53-MDM2-AR-AKT signalling network plays a critical role in the development and progression of prostate cancer. However, the molecular mechanisms regulating this signalling network are not completely defined. By conducting transcriptome analysis, denaturing immunoprecipitations and immunopathology, we demonstrate that the TP53-MDM2-AR-AKT cross-talk is regulated by the deubiquitinating enzyme USP12 in prostate cancer. Our findings explain why USP12 is one of the 12 most commonly overexpressed cancer-associated genes located near an amplified super-enhancer. We find that USP12 deubiquitinates MDM2 and AR, which in turn controls the levels of the TP53 tumour suppressor and AR oncogene in prostate cancer. Consequently, USP12 levels are predictive not only of cancer development but also of patient’s therapy resistance, relapse and survival. Therefore, our findings suggest that USP12 could serve as a promising therapeutic target in currently incurable castrate-resistant prostate cancer.

Publication metadata

Author(s): McClurg UL, Chit NCTH, Azizyan M, Edwards J, Nabbi A, Riabowol KT, Nakjang S, McCracken SR, Robson CN

Publication type: Article

Publication status: Published

Journal: Oncogene

Year: 2018

Volume: 37

Pages: 4679-4691

Online publication date: 14/05/2018

Acceptance date: 23/03/2018

Date deposited: 17/05/2018

ISSN (print): 0950-9232

ISSN (electronic): 1476-5594

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41388-018-0283-3

DOI: 10.1038/s41388-018-0283-3

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