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Regulation of miR-200c and miR-141 by methylation in prostate cancer

Lynch, Seodhna, O'Neill, Karla M., McKenna, Michael M., Walsh, CP and McKenna, Declan J (2016) Regulation of miR-200c and miR-141 by methylation in prostate cancer. The Prostate, 76 (13). pp. 1146-1159. [Journal article]

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URL: http://dx.doi.org/10.1002/pros.23201

DOI: doi:10.1002/pros.23201

Abstract

BACKGROUNDIn prostate cancer (PCa), abnormal expression of several microRNAs (miRNAs) has been previously reported. Increasing evidence shows that aberrant epigenetic regulation of miRNAs is a contributing factor to their altered expression in cancer. In this study, we investigate whether expression of miR-200c and miR-141 in PCa is related to the DNA methylation status of their promoter.METHODSPCR analysis of miR-200c and miR-141, and CpG methylation analysis of their common promoter, was performed in PCa cell-lines and in archived prostate biopsy specimens. The biological significance of miR-200c and miR-141 expression in prostate cancer cells was assessed by a series of in vitro bioassays and the effect on proposed targets DNMT3A and TET1/TET3 was investigated. The effect on promoter methylation status in cells treated with demethylating agents was also examined.RESULTSmiR-200c and miR-141 are both highly elevated in LNCaP, 22RV1, and DU145 cells, but significantly reduced in PC3 cells. This correlates inversely with the methylation status of the miR-200c/miR-141 promoter, which is unmethylated in LNCaP, 22RV1, and DU145 cells, but hypermethylated in PC3. In PC3 cells, miR-200c and miR-141 expression is subsequently elevated by treatment with the demethylating drug decitabine (5-aza-2′deoxycytidine) and by knockdown of DNA methyltransferase 1 (DNMT1), suggesting their expression is regulated by methylation. Expression of miR-200c and miR-141 in prostate biopsy tissue was inversely correlated with methylation in promoter CpG sites closest to the miR-200c/miR-141 loci. In vitro, over-expression of miR-200c in PC3 cells inhibited growth and clonogenic potential, as well as inducing apoptosis. Expression of the genes DNMT3A and TET1/TET3 were down-regulated by miR-200c and miR-141 respectively. Finally, treatment with the soy isoflavone genistein caused demethylation of the promoter CpG sites closest to the miR-200c/miR-141 loci resulting in increased miR-200c expression.CONCLUSIONSOur findings provide evidence that miR-200c and miR-141 are under epigenetic regulation in PCa cells. We propose that profiling their expression and methylation status may have potential as a novel biomarker or focus of therapeutic intervention in the diagnosis and prognosis of PCa.

Item Type:Journal article
Keywords:microRNA;miR-200c;miR-141;prostate cancer;DNA methylation
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute > Genomic Medicine
Biomedical Sciences Research Institute
ID Code:34694
Deposited By: Dr Declan McKenna
Deposited On:08 Jun 2016 09:09
Last Modified:17 Oct 2017 16:23

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