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.

中文翻译：

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甲基化相关的miR-193b沉默激活了侵略性前列腺癌的主要驱动程序。

miRNA的表观遗传沉默是癌症中miRNA异常表达的主要机制，并且据报道miRNA启动子的超甲基化有助于前列腺癌的发生和发展。最近的数据表明，与正常组织相比，miR-193b启动子在前列腺癌中甲基化程度较高，但是尚未进行评估其功能意义的研究。我们旨在阐明miR-193b的功能并确定其在前列腺癌中的关键靶标。我们在癌症基因组图谱（TCGA）队列中观察到miR-193b水平与其启动子的甲基化呈负相关。miR-193b在前列腺癌细胞系中的过表达抑制侵袭并诱导凋亡。我们发现，在脂肪肉瘤中过表达miR-193b时被下调的前150个基因中的大多数在转移性前列腺癌中过表达，并且41个miR-193b靶基因与侵略性前列腺癌亚型1（PCS1）签名中的86个基因重叠。miR-193b的过度表达导致前列腺癌细胞系中41个基因的大部分被抑制。41个基因的高表达与前列腺癌的复发相关。敲低miR-193b靶向表型复制的miR-193b过表达的前列腺癌细胞中的FOXM1和RRM2。DNA甲基转移酶（DNMT）和组蛋白脱乙酰基酶（HDAC）抑制剂的双重处理降低了miR-193b启动子甲基化并恢复了对FOXM1和RRM2的抑制。