Journal
ONCOGENE
Volume 32, Issue 23, Pages 2891-2899Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.300
Keywords
microRNA; miR-205; MED1; epigenetics; prostate cancer
Funding
- Cancer Institute NSW (CINSW)
- Cure Cancer Australia fellowships
- National Health and Medical Research Council
- CINSW project grants
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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.
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