Dataset Information

Methylation-associated miR-193b silencing activates master drivers of aggressive prostate cancer.

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.

SUBMITTER: Mazzu YZ

PROVIDER: S-EPMC6717747 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Methylation-associated miR-193b silencing activates master drivers of aggressive prostate cancer.

Mazzu Ying Z YZ Yoshikawa Yuki Y Nandakumar Subhiksha S Chakraborty Goutam G Armenia Joshua J Jehane Lina E LE Lee Gwo-Shu Mary GM Kantoff Philip W PW

Molecular oncology 20190719 9

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 can ...[more]

PMID: 31225930

Similar Datasets

Project description:Although there are molecularly distinct subtypes of prostate cancer, no molecular classification system is used clinically. The ribonucleotide reductase small subunit M2 (RRM2) gene plays an oncogenic role in many cancers. Our previous study elucidated comprehensive molecular mechanisms of RRM2 in prostate cancer (PC). Given the potent functions of RRM2, we set out to determine whether the RRM2 signature can be used to identify aggressive subtypes of PC. We applied gene ontology and pathway analysis in RNA-seq datasets from PC cells overexpressing RRM2. We refined the RRM2 signature by integrating it with two molecular classification systems (PCS and PAM50 subtypes) that define aggressive PC subtypes (PCS1 and luminal B) and correlated signatures with clinical outcomes in six published cohorts comprising 4000 cases of PC. Increased expression of genes in the RRM2 signature was significantly correlated with recurrence, high Gleason score, and lethality of PC. Patients with high RRM2 levels showed higher PCS1 score, suggesting the aggressive PC feature. Consistently, RRM2-regulated genes were highly enriched in the PCS1 signature from multiple PC cohorts. A simplified RRM2 signature (12 genes) was identified by intersecting the RRM2 signature, PCS1 signature, and the PAM50 classifier. Intriguingly, inhibition of RRM2 specifically targets PCS1 and luminal B genes. Furthermore, 11 genes in the RRM2 signature were correlated with enzalutamide resistance by using a single-cell RNA-seq dataset from PC circulating tumor cells. Finally, high expression of RRM2 was associated with an immunosuppressive tumor-immune microenvironment in both primary prostate cancer and metastatic prostate cancer using CIBERSORT analysis and LM22, a validated leukocyte gene signature matrix. These data demonstrate that RRM2 is a driver of aggressive prostate cancer subtypes and contributes to immune escape, suggesting that RRM2 inhibition may be of clinical benefit for patients with PC.

Dataset Information

Methylation-associated miR-193b silencing activates master drivers of aggressive prostate cancer.

Publications

Methylation-associated miR-193b silencing activates master drivers of aggressive prostate cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets