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

McClurg, U. L., Chit, N. C.T.H., Azizyan, M., Edwards, J. , Nabbi, A., Riabowol, K. T., Nakjang, S., McCracken, S. R. and Robson, C. N. (2018) Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12. Oncogene, 37, pp. 4679-4691. (doi: 10.1038/s41388-018-0283-3) (PMID:29755129)

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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.

Item Type:Articles
Additional Information:ULM, SRM and CNR were funded by PC UK (PG09-23), JGWP Foundation (BH142412) and JRE Scientific Committee Charity, Newcastle Healthcare Charity (JG/ML/0414). CNR is supported by Cancer Research UK (C27826/A15994). NCTHC was funded by Newcastle University.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Edwards, Professor Joanne
Authors: McClurg, U. L., Chit, N. C.T.H., Azizyan, M., Edwards, J., Nabbi, A., Riabowol, K. T., Nakjang, S., McCracken, S. R., and Robson, C. N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncogene
Publisher:Nature Publishing Group
ISSN:0950-9232
ISSN (Online):1476-5594
Published Online:14 May 2018
Copyright Holders:Copyright © 2018 Macmillan Publishers Limited
First Published:First published in Oncogene 37:4679-4691
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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