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

被引:136
作者
Neves R. [1 ]
Scheel C. [2 ]
Weinhold S. [1 ]
Honisch E. [3 ]
Iwaniuk K.M. [1 ]
Trompeter H.-I. [1 ]
Niederacher D. [3 ]
Wernet P. [1 ]
Santourlidis S. [1 ]
Uhrberg M. [1 ]
机构
[1] Institute for Transplantation Diagnostics and Cell Therapeutics, University Clinic Düsseldorf, Building 14.80, 40225 Düsseldorf
[2] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge
[3] Department of Gynaecology and Obstetrics, University Clinic Düsseldorf, Building 14.80, 40225 Düsseldorf
关键词
Invasive Breast Cancer Cell; Invasive Ductal Breast Carcinoma; Invasive Breast Cancer Cell Line; Human Immortalize Mammary Epithelial Cell; HMLE Cell;
D O I
10.1186/1756-0500-3-219
中图分类号
学科分类号
摘要
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. © 2010 Uhrberg et al; licensee BioMed Central Ltd.
引用
收藏
相关论文
共 32 条
[1]  
Thiery J.P., Epithelial-mesenchymal transitions in tumour progression, Nat Rev Cancer, 2, pp. 442-454, (2002)
[2]  
Park S.M., Gaur A.B., Lengyel E., Peter M.E., The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2, Genes Dev, 22, pp. 894-907, (2008)
[3]  
Korpal M., Lee E.S., Hu G., Kang Y., The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2, J Biol Chem, 283, pp. 14910-14914, (2008)
[4]  
Gregory P.A., Bert A.G., Paterson E.L., Barry S.C., Tsykin A., Farshid G., Vadas M.A., Khew-Goodall Y., Goodall G.J., The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1, Nat Cell Biol, 10, pp. 593-601, (2008)
[5]  
Bartel D.P., MicroRNAs: Target recognition and regulatory functions, Cell, 136, pp. 215-233, (2009)
[6]  
Esquela-Kerscher A., Slack F.J., Oncomirs - MicroRNAs with a role in cancer, Nat Rev Cancer, 6, pp. 259-269, (2006)
[7]  
Nam E.J., Yoon H., Kim S.W., Kim H., Kim Y.T., Kim J.H., Kim J.W., Kim S., MicroRNA Expression Profiles in Serous Ovarian Carcinoma, Clin Cancer Res, 14, pp. 2690-2695, (2008)
[8]  
Taylor D.D., Gercel-Taylor C., MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer, Gynecol Oncol, 110, pp. 13-21, (2008)
[9]  
Iorio M.V., Visone R., Di Leva G., Donati V., Petrocca F., Casalini P., Taccioli C., Volinia S., Liu C.G., Alder H., Et al., MicroRNA signatures in human ovarian cancer, Cancer Res, 67, pp. 8699-8707, (2007)
[10]  
Hurteau G.J., Carlson J.A., Spivack S.D., Brock G.J., Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin, Cancer Res, 67, pp. 7972-7976, (2007)