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

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. A recent genome wide association study reported that the A-allele of the rs4245739 SNP (A>C), located in the 3'UTR of MDM4, is associated with increased prostate cancer risk. Computational predictions revealed that the rs4245739 SNP is located within a predicted binding site for three microRNAs (miRNA): miR-191-5p, miR-887 and miR-3669. Here, 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 but rather 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 PC3 cell viability. This study is the first to demonstrate regulation of the MDM4 rs4245739 SNP C-allele by two miRNAs in prostate cancer, and thereby identifies a mechanism by which the MDM4 rs4245739 SNP A-allele may be associated with increased prostate cancer risk.