: Epithelial-to-Mesenchymal Transition (EMT) is involved in prostate cancer metastatic progression, and its plasticity suggests epigenetic implications. Deregulation of DNMTs and several 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 prostate cancer model obtained via exposure of PC3 cells to conditioned media from cancer-associated fibroblasts (CM-CAFs). 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 downregulated 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 toward 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 data set 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 involved in EMT in prostate cancer.

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

Rizzo, Francesca
Investigation
;
Giurato, Giorgio
Investigation
;
Weisz, Alessandro
Conceptualization
;
2021

Abstract

: Epithelial-to-Mesenchymal Transition (EMT) is involved in prostate cancer metastatic progression, and its plasticity suggests epigenetic implications. Deregulation of DNMTs and several 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 prostate cancer model obtained via exposure of PC3 cells to conditioned media from cancer-associated fibroblasts (CM-CAFs). 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 downregulated 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 toward 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 data set 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 involved in EMT in prostate cancer.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/4774412
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact