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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

Oncogene volume 33, pages 1325–1335 (2014)Cite this article

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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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Acknowledgements

This study was supported by grants from the Korea Healthcare Technology R&D Project (A101836), the Ministry of Health Welfare and Family Affairs and the Research Program for New Drug Target Discovery (2011-0030173).

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Author notes

  1. J-Y Lee and M K Park: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea

    J-Y Lee & G Kong

  2. College of Pharmacy, Dongguk University, Seoul, Korea

    M K Park, H J Lee & C H Lee

  3. Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea

    J-H Park, D H Shin & G Kong

  4. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Y Kang

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Lee, JY., Park, M., Park, JH. et al. 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. Oncogene 33, 1325–1335 (2014). https://doi.org/10.1038/onc.2013.53

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