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

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 immunopathol...

Full description

Saved in:
Bibliographic Details
Published in:Oncogene 2018-08, Vol.37 (34), p.4679-4691
Main Authors: McClurg, Urszula L., Chit, Nay C. T. H., Azizyan, Mahsa, Edwards, Joanne, Nabbi, Arash, Riabowol, Karl T., Nakjang, Sirintra, McCracken, Stuart R., Robson, Craig N.
Format: Article
Language:English
Subjects:
13/1
13/51
13/89
38/39
38/77
38/89
38/91
631/67/395
631/67/589/466
631/80/458/582
631/80/86/2363
96/109
AKT protein
Animals
Apoptosis
Cancer
Cancer genetics
Care and treatment
Cell Biology
Cell Line, Tumor
Cellular signal transduction
Chlorocebus aethiops
COS Cells
Development and progression
Enzymes
Gene expression
Genes
Genetic aspects
Health aspects
Human Genetics
Humans
Innovations
Internal Medicine
Male
MDM2 protein
Medical schools
Medicine
Medicine & Public Health
Molecular modelling
Molecular targeted therapy
Neoplasm Recurrence, Local - metabolism
Oncology
p53 Protein
Prostate cancer
Prostatic Neoplasms - metabolism
Proteases
Proto-Oncogene Proteins c-akt - metabolism
Proto-Oncogene Proteins c-mdm2 - metabolism
Receptors, Androgen - metabolism
Signal Transduction - physiology
Therapeutic applications
Tumor proteins
Tumor Suppressor Protein p53 - metabolism
Tumors
Ubiquitin Thiolesterase - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-018-0283-3