Loss of the polycomb protein Mel-18 enhances the epithelial-mesenchymal transition by ZEB1 and ZEB2 expression through the downregulation of miR-205 in breast cancer

Abstract

The epithelial?mesenchymal transition (EMT) is the pivotal mechanism underlying the initiation of cancer invasion and metastasis.Although Mel-18 has been implicated in several biological processes in cancer, its function in the EMT of human cancers has not yetbeen studied. Here, we demonstrate that Mel-18 negatively regulates the EMT by epigenetically modulating miR-205. We identifiedmiR-205 as a novel target of Mel-18 using a microRNA microarray analysis and found that Mel-18 increased miR-205 transcription bythe inhibition of DNA methyltransferase-mediated DNA methylation of the miR-205 promoter, thereby downregulating its targetgenes, ZEB1 and ZEB2. Furthermore, the loss of Mel-18 promoted ZEB1- and ZEB2-mediated downregulation of E-cadherintranscription and also enhanced the expression of mesenchymal markers, leading to increased migration and invasion in MCF-7cells. In MDA-MB-231 cells, Mel-18 overexpression restored E-cadherin expression, resulting in reduced migration and invasion.These effects were reversed by miR-205 overexpression or inhibition. A tumor xenograft with Mel-18 knockdown MCF-7 cellsconsistently showed increased ZEB1 and ZEB2 expression and decreased E-cadherin expression. Taken together, these resultssuggest that Mel-18 functions as a tumor suppressor by its novel negative control of the EMT, achieved through regulating theexpression of miR-205 and its target genes, ZEB1 and ZEB2.