DNMT3A epigenetically regulates key microRNAs involved in epithelial-to-mesenchymal transition in prostate cancer. (23rd October 2021)

• Record Type: Journal Article
• Authors: Mancini, Monica; Grasso, Margherita; Muccillo, Livio; Babbio, Federica; Precazzini, Francesca; Castiglioni, Ilaria; Zanetti, Valentina; Rizzo, Francesca; Pistore, Christian; De Marino, Maria Giovanna; Zocchi, Michele; Del Vescovo, Valerio; Licursi, Valerio; Giurato, Giorgio; Weisz, Alessandro; Chiarugi, Paola; Sabatino, Lina; Denti, Michela Alessandra; Bonapace, Ian Marc
• Is Part Of: Carcinogenesis. Volume 42:Number 12(2021)
• Page Start: 1449
• Page End: 1460
• Publication Date: 2021-10-23
• Subjects: Carcinogenesis -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Periodicals; 616.994071
• DOI: 10.1093/carcin/bgab101
• Languages: English
• ISSNs: 0143-3334

Abstract

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. Abstract : In an ex vivo prostate cancer model of EMT, DNMT3A determines promoter methylation of miRNAs regulating key EMT factors. Analysis of TCGA-PRAD patients with an EMT signature confirms these findings, supporting the role of DNMT3A in EMT and PCa progression.