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

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dc.contributor.authorStegeman, S.
dc.contributor.authorMoya, L.
dc.contributor.authorSelth, L.
dc.contributor.authorSpurdle, A.
dc.contributor.authorClements, J.
dc.contributor.authorBatra, J.
dc.date.issued2015
dc.descriptionAccepted Preprint first posted online on 10 February 2015
dc.description.abstractThe 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.
dc.description.statementofresponsibilityShane Stegeman, Leire Moya, Luke A. Selth, Amanda B. Spurdle, Judith A. Clements and Jyotsna Batra
dc.identifier.citationEndocrine-Related Cancer, 2015; 22(2):265-276
dc.identifier.doi10.1530/ERC-15-0013
dc.identifier.issn1351-0088
dc.identifier.issn1479-6821
dc.identifier.orcidSelth, L. [0000-0002-4686-1418]
dc.identifier.urihttp://hdl.handle.net/2440/89765
dc.language.isoen
dc.publisherBioScientifica
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1050742
dc.rights© 2015 by the Society for Endocrinology
dc.source.urihttps://doi.org/10.1530/erc-15-0013
dc.subjectMDM4
dc.subjectmicroRNA
dc.subjectsingle nucleotide polymorphism
dc.subjectprostate cancer
dc.titleA genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer
dc.typeJournal article
pubs.publication-statusPublished

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