Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California.
MiR-145 is downregulated in various cancers including prostate cancer. However, the underlying mechanisms of miR-145 downregulation are not fully understood. Here we reported that miR-145 was silenced through DNA hypermethylation and p53 mutation status in laser capture microdissected (LCM) prostate cancer and matched adjacent normal tissues. In 22 of 27 (81%) prostate tissues, miR-145 was significantly downregulated in the cancer compared to the normal tissues. Further studies on miR-145 downregulation mechanism showed that miR-145 is methylated at the promoter region in both prostate cancer tissues and 50 different types of cancer cell lines. In 7 cancer cell lines with miR-145 hypermethylation, 5-aza-2'-deoxycytidine treatment dramatically induced miR-145 expression. Interestingly, we also found a significant correlation between miR-145 expression and the status of p53 gene in both LCM prostate tissues and 47 cancer cell lines. In 29 cell lines with mutant p53, miR-145 levels were downregulated in 28 lines (97%) while in 18 cell lines with wild type p53, miR-145 levels were downregulated in only 6 lines (33%, p<0.001). EMSA showed that p53 binds to the p53 response element upstream of miR-145, but the binding was inhibited by hypermethylation. To further confirm that p53 binding to miR-145 could regulate miR-145 expression, we transfected WTp53 and MUTp53 into PC-3 cells and found that miR-145 is upregulated by WTp53, but not with MUTp53. The apoptotic cells are increased after WTp53 transfection. In summary, this is the first report documenting that downregulation of miR-145 is through DNA methylation and p53 mutation pathways in prostate cancer.
Written by:
Suh SO, Chen Y, Zaman MS, Hirata H, Yamamura S, Shahryari V, Liu J, Tabatabai ZL, Kakar S, Deng G, Tanaka Y, Dahiya R.
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Reference: Carcinogenesis. 2011 Feb 23. Epub ahead of print.
doi: 10.1093/carcin/bgr036
PubMed Abstract
PMID: 21349819
UroToday.com Prostate Cancer Section