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
- Authors
- Lee, J-Y; Park, M. K.; Park, J-H; Lee, H. J.; Shin, D. H.; Kang, Y.; Lee, C. H.; Kong, G.
- Issue Date
- Mar-2014
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- Mel-18; miR-205; ZEB1; ZEB2; epithelial-mesenchymal transition; polycomb
- Citation
- ONCOGENE, v.33, no.10, pp.1325 - 1335
- Indexed
- SCIE
SCOPUS
- Journal Title
- ONCOGENE
- Volume
- 33
- Number
- 10
- Start Page
- 1325
- End Page
- 1335
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/160544
- DOI
- 10.1038/onc.2013.53
- ISSN
- 0950-9232
- 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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