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Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer

Abstract

Deregulation of microRNA (miRNA) expression can have a critical role in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription is commonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene of unknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1, also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading to reduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression of miR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressor function. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease in miR-205 expression and an increase in MED1 expression in primary tumor samples (n=14), when compared with matched normal prostate (n=7). An expanded patient cohort (tumor n=149, matched normal n=30) also showed significant MIR-205 DNA methylation in tumors compared with normal, and MIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio=2.005, 95% confidence interval (1.109, 3.625), P=0.02), in patients with low preoperative prostate specific antigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressor that targets MED1 and may provide a potential biomarker in prostate cancer management.Oncogene advance online publication, 6 August 2012; doi:10.1038/onc.2012.300.

Type Journal
Authors Hulf, T.; Sibbritt, T.; Wiklund, E.D.; Patterson, K.; Song, J.Z.; Stirzaker, C.; Qu, W.; Nair, S.; Horvath, L.G.; Armstrong, N.J.; Kench, J.G.; Sutherland, R.L.; Clark, S.J.
Garvan Authors Dr Clare Stirzaker , Prof James Kench , Dr Jenny Song , Dr Kate Patterson , A/Prof Lisa Horvath , Dr Nicola Armstrong , Dr Shalima Nair , Prof Susan Clark , Dr Wenjia Qu
Publisher Name ONCOGENE
Published Date 2013-06-06 00:00:00
Published Volume 32
Published Issue 23
Published Pages 2891-9
URL http://www.ncbi.nlm.nih.gov/pubmed/22869146
Status Published