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

Oncogene
Urszula L McClurgCraig N Robson

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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Citations

Aug 6, 2020·International Journal of Environmental Research and Public Health·Alan A ArslanJoan Reibman
Mar 8, 2020·International Journal of Molecular Sciences·Da-Hye LeeKwang-Hyun Baek
Aug 27, 2019·Biochimica Et Biophysica Acta. Reviews on Cancer·Ji ChengWenyi Wei
Dec 11, 2020·NPJ Precision Oncology·Xuanrong ChenYuanjie Niu
May 1, 2021·Cancers·Giovana de Godoy FernandesCarlos Eduardo Fonseca-Alves
May 5, 2021·Cell Death and Differentiation·Yuling FuShengfeng Hu

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Methods Mentioned

BETA
ubiquitination
deubiquitination
immunoprecipitation
transfections

Software Mentioned

STAR2
R package pathview
pass
GOseq
Gencode
DEseq2
HTseq

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