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Role of DNA methylation in miR-200c/141 cluster silencing in invasive breast cancer cells

Rui Neves1, Christina Scheel2, Sandra Weinhold1, Ellen Honisch3, Katharina M Iwaniuk1, Hans-Ingo Trompeter1, Dieter Niederacher3, Peter Wernet1, Simeon Santourlidis1 and Markus Uhrberg1*

Author Affiliations

1 Institute for Transplantation Diagnostics and Cell Therapeutics, University Clinic Düsseldorf, Moorenstr. 5, Building 14.80, 40225 Düsseldorf, Germany

2 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA

3 Department of Gynaecology and Obstetrics, University Clinic Düsseldorf, Moorenstr. 5, Building 14.80, 40225 Düsseldorf, Germany

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BMC Research Notes 2010, 3:219  doi:10.1186/1756-0500-3-219

Published: 3 August 2010

Abstract

Background

The miR-200c/141 cluster has recently been implicated in the epithelial to mesenchymal transition (EMT) process. The expression of these two miRNAs is inversely correlated with tumorigenicity and invasiveness in several human cancers. The role of these miRNAs in cancer progression is based in part on their capacity to target the EMT activators ZEB1 and ZEB2, two transcription factors, which in turn repress expression of E-cadherin. Little is known about the regulation of the mir200c/141 cluster, whose targeting has been proposed as a promising new therapy for the most aggressive tumors.

Findings

We show that the miR-200c/141 cluster is repressed by DNA methylation of a CpG island located in the promoter region of these miRNAs. Whereas in vitro methylation of the miR-200c/141 promoter led to shutdown of promoter activity, treatment with a demethylating agent caused transcriptional reactivation in breast cancer cells formerly lacking expression of miR-200c and miR-141. More importantly, we observed that DNA methylation of the identified miR-200c/141 promoter was tightly correlated with phenotype and the invasive capacity in a panel of 8 human breast cancer cell lines. In line with this, in vitro induction of EMT by ectopic expression of the EMT transcription factor Twist in human immortalized mammary epithelial cells (HMLE) was accompanied by increased DNA methylation and concomitant repression of the miR-200c/141 locus.

Conclusions

The present study demonstrates that expression of the miR-200c/141 cluster is regulated by DNA methylation, suggesting epigenetic regulation of this miRNA locus in aggressive breast cancer cell lines as well as untransformed mammary epithelial cells. This epigenetic silencing mechanism might represent a novel component of the regulatory circuit for the maintenance of EMT programs in cancer and normal cells.