title: A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer.
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.
authors: School of Biomedical SciencesInstitute of Health and Biomedical Innovation, Translational Research Institute Pty Ltd, Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, Queensland 4102, AustraliaDame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, Adelaide Prostate Cancer Research CentreSchool of MedicineFreemasons Foundation Centre for Men's Health, The University of Adelaide, Adelaide, South Australia 5005, AustraliaMolecular Cancer Epidemiology LaboratoryGenetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors: Shane
authors: S
authors: Stegeman
authors: School of Biomedical SciencesInstitute of Health and Biomedical Innovation, Translational Research Institute Pty Ltd, Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, Queensland 4102, AustraliaDame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, Adelaide Prostate Cancer Research CentreSchool of MedicineFreemasons Foundation Centre for Men's Health, The University of Adelaide, Adelaide, South Australia 5005, AustraliaMolecular Cancer Epidemiology LaboratoryGenetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors: Leire
authors: L
authors: Moya
authors: School of Biomedical SciencesInstitute of Health and Biomedical Innovation, Translational Research Institute Pty Ltd, Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, Queensland 4102, AustraliaDame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, Adelaide Prostate Cancer Research CentreSchool of MedicineFreemasons Foundation Centre for Men's Health, The University of Adelaide, Adelaide, South Australia 5005, AustraliaMolecular Cancer Epidemiology LaboratoryGenetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia School of Biomedical SciencesInstitute of Health and Biomedical Innovation, Translational Research Institute Pty Ltd, Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, Queensland 4102, AustraliaDame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, Adelaide Prostate Cancer Research CentreSchool of MedicineFreemasons Foundation Centre for Men's Health, The University of Adelaide, Adelaide, South Australia 5005, AustraliaMolecular Cancer Epidemiology LaboratoryGenetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors: Luke A
authors: LA
authors: Selth
authors: School of Biomedical SciencesInstitute of Health and Biomedical Innovation, Translational Research Institute Pty Ltd, Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, Queensland 4102, AustraliaDame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, Adelaide Prostate Cancer Research CentreSchool of MedicineFreemasons Foundation Centre for Men's Health, The University of Adelaide, Adelaide, South Australia 5005, AustraliaMolecular Cancer Epidemiology LaboratoryGenetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors: Amanda B
authors: AB
authors: Spurdle
authors: School of Biomedical SciencesInstitute of Health and Biomedical Innovation, Translational Research Institute Pty Ltd, Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, Queensland 4102, AustraliaDame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, Adelaide Prostate Cancer Research CentreSchool of MedicineFreemasons Foundation Centre for Men's Health, The University of Adelaide, Adelaide, South Australia 5005, AustraliaMolecular Cancer Epidemiology LaboratoryGenetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors: Judith A
authors: JA
authors: Clements
authors: School of Biomedical SciencesInstitute of Health and Biomedical Innovation, Translational Research Institute Pty Ltd, Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, Queensland 4102, AustraliaDame Roma Mitchell Cancer Research LaboratoriesSchool of Medicine, Adelaide Prostate Cancer Research CentreSchool of MedicineFreemasons Foundation Centre for Men's Health, The University of Adelaide, Adelaide, South Australia 5005, AustraliaMolecular Cancer Epidemiology LaboratoryGenetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia jyotsna.batra@qut.edu.au.
authors: Jyotsna
authors: J
authors: Batra
mesh_terms: D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; C546177:MIRN191 microRNA, human; C000603103:MIRN887 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins
keywords: MDM4; microRNA; prostate cancer; single nucleotide polymorphism