Epigenetic silencing of miR-200c in breast cancer is associated with aggressiveness and is modulated by ZEB1

Valentina Damiano, Giulia Brisotto, Silvia Borgna, Alessandra di Gennaro, Michela Armellin, Tiziana Perin, Michela Guardascione, Roberta Maestro, Manuela Santarosa

Research output: Contribution to journalArticlepeer-review

Abstract

Loss of expression of miR-200 family members has been implicated in cellular plasticity, a phenomenon that accounts for epithelial-to-mesenchymal transition (EMT) and stem-like features of many carcinomas and is considered a major cause of tumor aggressiveness and drug resistance. Nevertheless, the mechanisms of miR-200 downregulation in breast cancer are still largely unknown. Here we show that miR-200c expression inversely correlates with miR-200c/miR-141 locus methylation in triple-negative breast tumors (TNBC). Importantly, low levels of miR-200c expression and high levels of miR-200c/miR-141 locus methylation associated with lymph node metastasis. Moreover, miR-200c/miR-141 locus methylation was significantly related to high expression of ZEB1 in two independent TNBC series. Silencing of ZEB1 in vitro reduced miR-200c/miR-141 DNA methylation and, concurrently, decreased histone H3K9 trimethylation. This chromatin modifications were paralleled by an increase in the expression of both miR-200c and E-cadherin. Similar effects were achieved by treatment with a demethylating agent. Our data suggest that gene methylation is an important element in the regulation of the miR-200c/ZEB1 axis and that chromatin remodeling of the miR-200c/miR-141 locus is affected by ZEB1 and, thus, contributes to ZEB1-induced cellular plasticity.

Original languageEnglish
Pages (from-to)147-158
Number of pages12
JournalGenes Chromosomes and Cancer
Volume56
Issue number2
DOIs
Publication statusPublished - Feb 1 2017

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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