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

Oncogene volume 37, pages 4679–4691 (2018)Cite this article

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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.

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Acknowledgements

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.

Author contributions

ULM and CNR designed the study; ULM, NCTHC and MA performed the experiments; ULM and SRM scored and analysed all of the pathology data, ULM, AN and KTR analysed the TCGA dataset; SN and ULM analysed the RNA sequencing data; JE provided the Glasgow patient cohort; ULM prepared the manuscript with input from all authors.

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Authors and Affiliations

  1. Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

    Urszula L. McClurg, Nay C. T. H. Chit, Mahsa Azizyan, Sirintra Nakjang, Stuart R. McCracken & Craig N. Robson

  2. Institute of Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

    Urszula L. McClurg

  3. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH, Scotland, UK

    Joanne Edwards

  4. Department of Oncology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, Canada

    Arash Nabbi & Karl T. Riabowol

  5. Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

    Sirintra Nakjang

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  1. Urszula L. McClurg
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Correspondence to Urszula L. McClurg or Craig N. Robson.

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McClurg, U.L., Chit, N.C.T.H., Azizyan, M. et al. Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12. Oncogene 37, 4679–4691 (2018). https://doi.org/10.1038/s41388-018-0283-3

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