Abstract
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.
Highlights
Epigenetic mechanisms of gene expression regulation, including DNA methylation, histone modifications, and small noncoding microRNA, play critical roles in cancer initiation and progression (Suva et al, 2013)
We assessed the expression of miR-193b by quantitative reverse transcription PCR and the methylation status of the miR-193b promoter by methylation-specific PCR (MSP) in 7 human prostate cancer (PC) cell lines and 2 immortalized prostate epithelial cell lines (Fig. 1B,C)
E-Cadherin N-Cadherin β-Actin ontology analysis and gene set enrichment analysis (GSEA), we demonstrated that the 150 miR-193b-regulated genes were significantly enriched in the FOXM1 pathway and that 7 of the 41 genes are in the FOXM1 pathway (Fig. 3E)
Summary
Epigenetic mechanisms of gene expression regulation, including DNA methylation, histone modifications, and small noncoding microRNA (miRNA), play critical roles in cancer initiation and progression (Suva et al, 2013). Aberrant epigenetic regulation can cause altered gene expression and malignant cellular transformation. MiRNA regulate a wide range of biological processes by repressing the expression of target genes. Abbreviations 5-Aza-dC, 5-Aza-2’-deoxycytidine; DNMT, DNA methyltransferase; DNMTi, DNA methyltransferase inhibitor; GSEA, gene set enrichment analysis; HDAC, histone deacetylase; HDACi, histone deacetylase inhibitor; miRNA, small noncoding microRNA; MSP, methylation-specific PCR; PC, prostate cancer; PCS1, prostate cancer subtype 1; TCGA, The Cancer Genome Atlas. Growing evidence has demonstrated that miRNA can be epigenetically silenced in various cancers (Suzuki et al, 2012), including by methylation at CpG regions within miRNA promoters (Weber et al, 2007)
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