3,6-Dihydroxyflavone suppresses breast carcinogenesis by epigenetically regulating miR-34a and miR-21
Menée sur des lignées cellulaires et à l'aide de modèles murins, cette étude montre que la 3,6-dihydroxyflavone inhibe la carcinogenèse mammaire en régulant l'expression des microARNs miR-34a et miR-21 via un mécanisme épigénétique
Our previous study selected a promising chemopreventive agent 3,6-dihydroxyflavone (3,6-DHF), and found 3,6-DHF significantly up-regulates miR-34a and down-regulates miR-21 in breast carcinogenesis, yet the upstream and downstream events of the anticancer mechanism remain unclear. The present study showed that 3,6-DHF co-treatment effectively inhibits carcinogens-induced breast carcinogenic transformation in human breast epithelial MCF10A cells. The data revealed the significant down-regulation of miR-34a and up-regulation of miR-21 in breast carcinogenesis, which could be mitigated by 3,6-DHF treatment. Methylation-Specific PCR detections showed that 3,6-DHF inhibits the hypermethylation of the miR-34a promoter. Further studies indicated that 3,6-DHF is an effective methyltransferase (DNMT)1 inhibitor, docking to the putative cytosine pocket of the protein, and thus decreases the DNMT activity in a dose-dependent manner. Moreover, the ChIP-qPCR analysis for histone modifications showed that 3,6-DHF treatment significantly lowers the H3K9-14ac on the miR-21 promoter. Additionally, our study revealed that 3,6-DHF represses the PI3K/Akt/mTOR signaling pathway in breast carcinogenesis in vitro and in vivo. Inhibition of miR-34a or over-expression of miR-21 significantly reduced the effects of 3,6-DHF on Notch-1 and PTEN, and consequently weakened the suppression of 3,6-DHF on PI3K/Akt/mTOR. We concluded that 3,6-DHF up-regulates miR-34a via inhibiting DNMT1 and hypermethylation, while down-regulates miR-21 by modulating histone modification, and consequently suppresses the PI3K/Akt/mTOR signaling pathway in breast carcinogenesis.