期刊
EPIGENETICS
卷 7, 期 8, 页码 940-949出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/epi.21236
关键词
DNA methylation; miR-29a; miR-1256; isoflavone; TRIM68; PGK-1
资金
- National Cancer Institute, NIH [5R01CA083695, 5R01CA108535]
The epigenetic regulation of genes has long been recognized as one of the causes of prostate cancer (PC a) development and progression. Recent studies have shown that a number of microRNAs (miRNAs) are also epigenetically regulated in different types of cancers including PC a. In this study, we found that the DNA sequence of the promoters of miR-29a and miR-1256 are partly methylated in PC a cells, which leads to their lower expression both in PC a cells and in human tumor tissues compared with normal epithelial cells and normal human prostate tissues. By real-time PC R, Western Blot analysis and miRNA mimic and 3'-UTR-Luc transfection, we found that TRIM68 is a direct target of miR-29a and miR-1256 and that the downregulation of miR-29a and miR-1256 in PCa cells leads to increased expression of TRIM68 and PGK-1 in PCa cells and in human tumor tissue specimens. Interestingly, we found that a natural agent, isoflavone, could demethylate the methylation sites in the promoter sequence of miR-29a and miR-1256, leading to the upregulation of miR-29a and miR-1256 expression. The increased levels of miR-29a and miR-1256 by isoflavone treatment resulted in decreased expression of TRIM68 and PGK-1, which is mechanistically linked with inhibition of PCa cell growth and invasion. The selective demethylation activity of isoflavone on miR-29a and miR-1256 leading to the suppression of TRIM68 and PGK-1 expression is an important biological effect of isoflavone, suggesting that isoflavone could be a useful non-toxic demethylating agent for the prevention of PCa development and progression.
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