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 tumoursuppressive functions. As part of a recent genome-wide association study it was determined that the A-allele of the rs4245739 SNP (AOC), located in the 3 0 -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.Key Words " MDM4" microRNA " single nucleotide polymorphism " prostate cancer

The MDM4 SNP34091 (rs4245739) C-allele is associated with increased risk of ovarian—but not endometrial cancer

“…Although risk assessments are not directly comparable to survival analysis, our findings may seem somewhat contradictory to the report of the SNP34091A allele as a risk factor for recurrence and tumor-related death in ovarian cancer patients [20]. While the SNP34091A allele has been reported to confer higher MDM4 levels in ovarian [20] and prostate cancer cells [19], and the common assumption is that the oncogenic effect of high MDM4 levels is through the p53 pathway [31], it has been reported that over 90 % of all HGSOC have mutations in the TP53 gene [32]. Thus, it may be that the effect of MDM4 SNP34091 on ovarian cancer risk is mediated via additional pathways, other than p53.…”

“…Further, they reported the SNP rs1563828T allele, which is in LD with the SNP34091A allele among Caucasians, to be associated with early onset of both familial and sporadic ovarian cancer [16]. To the best of our knowledge, the biological effects of SNP rs1563828 have not been elucidated; thus, the possibility exist that it may be SNP34091, which is known to have a biological effect [19, 20], that contributes to the observed effect of SNP rs1563828 previously reported by Atwal and colleagues.…”

“…Recently, a single nucleotide polymorphism (SNP) in the MDM4 3’ untranslated region, MDM4 SNP34091A > C (rs4245739) was reported to affect MDM4 messenger RNA (mRNA) stability and protein levels [19, 20]. The SNP34091C variant creates a functional target site for hsa-miR-191, and both ovarian and prostate cancer cells harboring the C- allele displayed reduced MDM4 mRNA and protein levels [19, 20]. …”

A PRISMA-compliant meta-analysis of MDM4 genetic variants and cancer susceptibility

“…Recently, a single nucleotide polymorphism (SNP) in the 3′ untranslated region of the MDM4 gene, rs4245739 A > C has been found to affect MDM4 mRNA stability and protein levels [4]. Genotype AA was recorded to be more frequent in patients with high-grade than low-grade ovarian carcinoma [5].…”

MicroRNA Theranostics in Prostate Cancer Precision Medicine

“…A large-scale analysis of genetic variants in miRNA binding sites identified 22 prostate cancer risk associated miRSNPs, the 2 most significant miRSNPs being KLK3 (kallikrein related peptidase 3) rs1058205 (TϾC) and VAMP8 (vesicle associated membrane protein 8) rs1010 (AϾG), which were targeted by miR-3162-5p and miR-370 -5p respectively in an allele specific manner (77 ). Similarly, the C allele of the rs4245739 SNP (AϾC) located in the 3ЈUTR of the MDM4 (MDM4 p53 regulator) oncogene is a target of miR-191-5p and miR-887 resulting in prostate cancer protection (78 ). Therefore, in addition to miRNA expression profiles, cancer diagnosis and therapeutics may rely on the presence of miRSNPs in either precursor miRNAs, mature miRNAs or in 3Ј UTRs of miRNA target genes.…”