Stegeman, S.Moya, L.Selth, L.Spurdle, A.Clements, J.Batra, J.2015-03-122015-03-122015Endocrine-Related Cancer, 2015; 22(2):265-2761351-00881479-6821http://hdl.handle.net/2440/89765Accepted Preprint first posted online on 10 February 2015The 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.en© 2015 by the Society for EndocrinologyMDM4microRNAsingle nucleotide polymorphismprostate cancerJournal article003002273610.1530/ERC-15-00130003546241000162-s2.0-84929315369173417Selth, L. [0000-0002-4686-1418]