: 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.

DNMT3A epigenetically regulates key microRNAs involved in epithelial-to-mesenchymal transition in prostate cancer / 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. - In: CARCINOGENESIS. - ISSN 0143-3334. - ELETTRONICO. - 42:12(2021), pp. 1449-1460. [10.1093/carcin/bgab101]

DNMT3A epigenetically regulates key microRNAs involved in epithelial-to-mesenchymal transition in prostate cancer

Grasso, Margherita;Precazzini, Francesca;Castiglioni, Ilaria;Del Vescovo, Valerio;Denti, Michela Alessandra;
2021-01-01

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.
2021
12
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
DNMT3A epigenetically regulates key microRNAs involved in epithelial-to-mesenchymal transition in prostate cancer / 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. - In: CARCINOGENESIS. - ISSN 0143-3334. - ELETTRONICO. - 42:12(2021), pp. 1449-1460. [10.1093/carcin/bgab101]
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