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- Title
Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer.
- 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
- 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.
- Subjects
PROSTATE cancer prognosis; MICRORNA; EPIGENETICS; CARCINOGENESIS; GENE targeting; BIOMARKERS; CONFIDENCE intervals
- Publication
Oncogene, 2013, Vol 32, Issue 23, p2891
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2012.300