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A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer

Shane Stegeman1, Leire Moya1, Luke A Selth2

  • 1School of Biomedical SciencesInstitute of Health and Biomedical Innovation, Translational Research Institute Pty Ltd, Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, Queensland 4102, AustraliaDame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, Adelaide Prostate Cancer Research CentreSchool of MedicineFreemasons Foundation Centre for Men's Health, The University of Adelaide, Adelaide, South Australia 5005, AustraliaMolecular Cancer Epidemiology LaboratoryGenetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.

Endocrine-Related Cancer
|February 12, 2015
PubMed

Insights

The oncogene MDM4 is linked to increased prostate cancer risk via the rs4245739 SNP. Specific microRNAs target the C-allele, inhibiting MDM4 translation and affecting cancer progression.

Area of Science:

  • Molecular Biology
  • Genetics
  • Oncology

Background:

  • The MDM4 oncogene (also known as MDMX or HDMX) plays a role in cancer by suppressing tumor-suppressive genes.
  • A genome-wide association study identified the rs4245739 SNP (A>C) in MDM4's 3'-UTR, with the A-allele associated with higher prostate cancer risk.

Purpose of the Study:

  • To investigate the functional impact of the rs4245739 SNP on MDM4 regulation by microRNAs (miRNAs) in prostate cancer.
  • To elucidate the mechanism by which the rs4245739 SNP A-allele might contribute to prostate cancer susceptibility.

Main Methods:

  • Reporter gene assays and endogenous MDM4 expression analysis were used to assess miRNA binding and effects.
  • Computational predictions identified potential miRNA binding sites at the rs4245739 SNP.
  • Analysis of patient gene expression datasets correlated MDM4 with prostate cancer progression and metastasis.

Main Results:

  • miR-191-5p and miR-887 specifically bind to the rs4245739 SNP C-allele in prostate cancer cells.
  • These miRNAs inhibit MDM4 translation, not mRNA levels, in C-allele-containing PC3 cells.
  • MDM4 expression correlates with metastasis and progression; targeting MDM4 with miR-191-5p or miR-887 reduces PC3 cell viability.

Conclusions:

  • This study demonstrates miRNA-mediated regulation of the MDM4 rs4245739 SNP C-allele in prostate cancer.
  • A mechanism is identified where specific miRNAs targeting the C-allele may explain the association of the A-allele with increased prostate cancer risk.
Keywords:
MDM4microRNAprostate cancersingle nucleotide polymorphism

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