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Oncogene. 2014 Mar 6;33(10):1325-35. doi: 10.1038/onc.2013.53. Epub 2013 Mar 11.

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.

Author information

  • 1Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea.
  • 2College of Pharmacy, Dongguk University, Seoul, Korea.
  • 3Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
  • 4Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
  • 51] Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea [2] Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.

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.

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