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

Urszula L McClurg1,2, Nay C T H Chit3, Mahsa Azizyan3

  • 1Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. Urszula.McClurg@ncl.ac.uk.

Oncogene
|May 15, 2018
PubMed

Insights

The deubiquitinating enzyme USP12 regulates the TP53-MDM2-AR-AKT network in prostate cancer. USP12 targets MDM2 and AR, impacting tumor suppressor and oncogene levels, and predicts patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The TP53-MDM2-AR-AKT signaling network is crucial in prostate cancer development and progression.
  • The precise molecular mechanisms governing this critical signaling network remain incompletely understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of the TP53-MDM2-AR-AKT signaling network in prostate cancer.
  • To investigate the role of the deubiquitinating enzyme USP12 in prostate cancer pathogenesis.

Main Methods:

  • Transcriptome analysis
  • Denaturing immunoprecipitations
  • Immunopathology studies

Main Results:

  • Demonstrated that USP12 regulates the TP53-MDM2-AR-AKT signaling cross-talk in prostate cancer.
  • USP12 deubiquitinates both MDM2 and AR, thereby controlling TP53 tumor suppressor and AR oncogene levels.
  • USP12 overexpression correlates with amplified super-enhancers and is among the top 12 cancer-associated genes.

Conclusions:

  • USP12 levels are predictive of prostate cancer development, therapy resistance, relapse, and patient survival.
  • USP12 represents a potential therapeutic target for castrate-resistant prostate cancer.

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