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Type: Journal article
Title: A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer
Author: Stegeman, S.
Moya, L.
Selth, L.
Spurdle, A.
Clements, J.
Batra, J.
Citation: Endocrine-Related Cancer, 2015; 22(2):265-276
Publisher: BioScientifica
Issue Date: 2015
ISSN: 1351-0088
Statement of
Shane Stegeman, Leire Moya, Luke A. Selth, Amanda B. Spurdle, Judith A. Clements and Jyotsna Batra
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.
Keywords: MDM4
single nucleotide polymorphism
prostate cancer
Description: Accepted Preprint first posted online on 10 February 2015
Rights: © 2015 by the Society for Endocrinology
DOI: 10.1530/ERC-15-0013
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