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

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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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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