1. DNMT3A epigenetically regulates key microRNAs involved in epithelial-to-mesenchymal transition in prostate cancer.
- Author
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Mancini M, Grasso M, Muccillo L, Babbio F, Precazzini F, Castiglioni I, Zanetti V, Rizzo F, Pistore C, De Marino MG, Zocchi M, Del Vescovo V, Licursi V, Giurato G, Weisz A, Chiarugi P, Sabatino L, Denti MA, and Bonapace IM
- Subjects
- Binding Sites, Chromatin Immunoprecipitation, Computational Biology methods, DNA Methylation, Disease Susceptibility, Humans, Male, Promoter Regions, Genetic, Prostatic Neoplasms pathology, Protein Binding, RNA Interference, Tumor Microenvironment drug effects, Tumor Microenvironment genetics, DNA Methyltransferase 3A metabolism, Epigenesis, Genetic, Epithelial-Mesenchymal Transition genetics, Gene Expression Regulation, Neoplastic, MicroRNAs genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism
- Abstract
Epithelial-to-mesenchymal transition (EMT) is involved in prostate cancer (PCa) metastatic progression, and its plasticity suggests epigenetic implications. Deregulation of DNA methyltransferases (DNMTs) and several microRNAs (miRNAs) plays a relevant role in EMT, but their interplay has not been clarified yet. In this study, we provide evidence that DNMT3A interaction with several miRNAs has a central role in an ex vivo EMT PCa model obtained via exposure of PC3 cells to conditioned media from cancer-associated fibroblasts. The analysis of the alterations of the miRNA profile shows that miR-200 family (miR-200a/200b/429, miR-200c/141), miR-205 and miR-203, known to modulate key EMT factors, are down-regulated and hyper-methylated at their promoters. DNMT3A (mainly isoform a) is recruited onto these miRNA promoters, coupled with the increase of H3K27me3/H3K9me3 and/or the decrease of H3K4me3/H3K36me3. Most interestingly, our results reveal the differential expression of two DNMT3A isoforms (a and b) during ex vivo EMT and a regulatory feedback loop between miR-429 and DNMT3A that can promote and sustain the transition towards a more mesenchymal phenotype. We demonstrate the ability of miR-429 to target DNMT3A 3'UTR and modulate the expression of EMT factors, in particular ZEB1. Survey of the PRAD-TCGA dataset shows that patients expressing an EMT-like signature are indeed characterized by down-regulation of the same miRNAs with a diffused hyper-methylation at miR-200c/141 and miR-200a/200b/429 promoters. Finally, we show that miR-1260a also targets DNMT3A, although it does not seem to be involved in EMT in PCa., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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