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

• Published in: Endocrine-related cancer Vol. 22; no. 2; pp. 265 - 276
• Main Authors: Stegeman, Shane, Moya, Leire, Selth, Luke A, Spurdle, Amanda B, Clements, Judith A, Batra, Jyotsna
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.04.2015
• Subjects: Cell Line, Tumor; Disease Progression; Female; Humans; Male; MicroRNAs - genetics; MicroRNAs - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Ovarian Neoplasms - genetics; Polymorphism, Single Nucleotide; Prostate - metabolism; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; microRNA; prostate cancer; MDM4; single nucleotide polymorphism
• ISSN: 1351-0088; 1479-6821
• DOI: 10.1530/ERC-15-0013

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.