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

Shane Stegeman, Leire Moya, Luke A. Selth, Amanda B Spurdle, Judith A. Clements, Jyotsna Batra

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

The oncogene MDM4, also known as MDMX or HDMX, contributes to cancer susceptibility and progression through its capacity to negatively regulate a range of genes with tumour-suppressive functions. As part of a recent genome-wide association study it was determined that the A-allele of the rs4245739 SNP (A>C), located in the 3′-UTR of MDM4, is associated with an increased risk of prostate cancer. Computational predictions revealed that the rs4245739 SNP is located within a predicted binding site for three microRNAs (miRNAs): miR-191-5p, miR-887 and miR-3669. Herein, we show using reporter gene assays and endogenous MDM4 expression analyses that miR-191-5p and miR-887 have a specific affinity for the rs4245739 SNP C-allele in prostate cancer. These miRNAs do not affect MDM4 mRNA levels, rather they inhibit its translation in C-allele-containing PC3 cells but not in LNCaP cells homozygous for the A-allele. By analysing gene expression datasets from patient cohorts, we found that MDM4 is associated with metastasis and prostate cancer progression and that targeting this gene with miR-191-5p or miR-887 decreases in PC3 cell viability. This study is the first, to our knowledge, to demonstrate regulation of the MDM4 rs4245739 SNP C-allele by two miRNAs in prostate cancer, and thereby to identify a mechanism by which the MDM4 rs4245739 SNP A-allele may be associated with an increased risk for prostate cancer.

Original languageEnglish
Pages (from-to)265-276
Number of pages12
JournalEndocrine-Related Cancer
Volume22
Issue number2
DOIs
Publication statusPublished - 1 Apr 2015
Externally publishedYes

Keywords

  • MDM4
  • MicroRNA
  • Prostate cancer
  • Single nucleotide polymorphism

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