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

Stegeman, Shane, Moya, Leire, Selth, Luke A., Spurdle, Amanda B., Clements, Judith, & Batra, Jyotsna (2015) A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer. Endocrine Related Cancer, 22(2), pp. 265-276.

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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.

Impact and interest:

15 citations in Scopus
13 citations in Web of Science®
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ID Code: 90529
Item Type: Journal Article
Refereed: Yes
Keywords: MDM4, microRNA, prostate cancer, single nucleotide polymorphism
DOI: 10.1530/ERC-15-0013
ISSN: 1479-6821
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright © 2015 by the Society for Endocrinology
Deposited On: 22 Nov 2015 23:33
Last Modified: 23 Nov 2015 22:11

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