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

J. Y. Lee, M. K. Park, J. H. Park, H. J. Lee, D. H. Shin, Y. Kang, C. H. Lee, G. Kong

Research output: Contribution to journalArticle

73 Scopus citations

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 yet been studied. Here, we demonstrate that Mel-18 negatively regulates the EMT by epigenetically modulating miR-205. We identified miR-205 as a novel target of Mel-18 using a microRNA microarray analysis and found that Mel-18 increased miR-205 transcription by the inhibition of DNA methyltransferase-mediated DNA methylation of the miR-205 promoter, thereby downregulating its target genes, ZEB1 and ZEB2. Furthermore, the loss of Mel-18 promoted ZEB1- and ZEB2-mediated downregulation of E-cadherin transcription and also enhanced the expression of mesenchymal markers, leading to increased migration and invasion in MCF-7 cells. 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 cells consistently showed increased ZEB1 and ZEB2 expression and decreased E-cadherin expression. Taken together, these results suggest that Mel-18 functions as a tumor suppressor by its novel negative control of the EMT, achieved through regulating the expression of miR-205 and its target genes, ZEB1 and ZEB2.

Original languageEnglish (US)
Pages (from-to)1325-1335
Number of pages11
JournalOncogene
Volume33
Issue number10
DOIs
StatePublished - Mar 2014

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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