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Methylation‐associated miR‐193b silencing activates master drivers of aggressive prostate cancer
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Methylation‐associated miR‐193b silencing activates master drivers of aggressive prostate cancer
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Journal Article
Methylation‐associated miR‐193b silencing activates master drivers of aggressive prostate cancer
2019
Overview
Epigenetic silencing of miRNA is a primary mechanism of aberrant miRNA expression in cancer, and hypermethylation of miRNA promoters has been reported to contribute to prostate cancer initiation and progression. Recent data have shown that the miR‐193b promoter is hypermethylated in prostate cancer compared with normal tissue, but studies assessing its functional significance have not been performed. We aimed to elucidate the function of miR‐193b and identify its critical targets in prostate cancer. We observed an inverse correlation between miR‐193b level and methylation of its promoter in The Cancer Genome Atlas (TCGA) cohort. Overexpression of miR‐193b in prostate cancer cell lines inhibited invasion and induced apoptosis. We found that a majority of the top 150 genes downregulated when miR‐193b was overexpressed in liposarcoma are overexpressed in metastatic prostate cancer and that 41 miR‐193b target genes overlapped with the 86 genes in the aggressive prostate cancer subtype 1 (PCS1) signature. Overexpression of miR‐193b led to the inhibition of the majority of the 41 genes in prostate cancer cell lines. High expression of the 41 genes was correlated with recurrence of prostate cancer. Knockdown of miR‐193b targets FOXM1 and RRM2 in prostate cancer cells phenocopied overexpression of miR‐193b. Dual treatment with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors decreased miR‐193b promoter methylation and restored inhibition of FOXM1 and RRM2. Our data suggest that silencing of miR‐193b through promoter methylation may release the inhibition of PCS1 genes, contributing to prostate cancer progression and suggesting a possible therapeutic strategy for aggressive prostate cancer. In this study, we demonstrate that methylation‐associated miR‐193b silencing in prostate cancer leads to aberrant upregulation of genes associated with aggressive disease. Among them, FOXM1 and RRM2 are direct miR‐193b targets that promote invasion and survival. Pharmacologic inhibition of DNA methylation restores miR‐193b tumor suppressive function and could be a therapeutic strategy for the treatment of aggressive prostate cancer.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
Subject
/ Cancer
/ DNA
/ Forkhead Box Protein M1 - genetics
/ Forkhead Box Protein M1 - metabolism
/ FOXM1
/ Genes
/ Genomes
/ Genomics
/ Humans
/ Male
/ MicroRNA
/ miRNA
/ miR‐193b
/ Neoplasm Proteins - genetics
/ Neoplasm Proteins - metabolism
/ Prostatic Neoplasms - genetics
/ Prostatic Neoplasms - metabolism
/ Prostatic Neoplasms - pathology
/ Proteins
/ Ribonucleoside Diphosphate Reductase - genetics
/ Ribonucleoside Diphosphate Reductase - metabolism
/ RRM2
/ Scientific equipment and supplies industry
/ Tumors
