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

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• 作者：Valentina Damiano ; Giulia Brisotto ; Silvia Borgna ; Alessandra di Gennaro ; Michela Armellin ; Tiziana Perin ; Michela Guardascione ; Roberta Maestro and Manuela Santarosa
• 刊名：Genes, Chromosomes and Cancer
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：56
• 期：2
• 页码：147-158
• 全文大小：2063K
• ISSN：1098-2264

文摘

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.