H3K36me3-coupled DNA Demethylation by DNMT3A Is Essential for Hypoxia-Induced EMT of Cancer Cells [ChIP-Seq]

The epithelial-to-mesenchymal transition (EMT) and metastasis of the cancer cells are closely associated with epigenetic changes of chromatin and reprogramming of transcriptomes. The DNA methyltransferases DNMT3A and DNMT3B possess DNA demethylation/dehydroxymethylation activities. Here, we show, by a range of molecular/cellular approaches, that active DNA demethylation activity of DNMT3A is required for hypoxia-induced EMT of the primary colon carcinoma SW480 cells, its genome-wide DNA demethylation, and promoter DNA demethylation/transcriptional activation of the EMT genes TWIST1 and SNAIL1. DNMT3A also positively regulates hypoxia-induced TWIST1 activation in other types of cancer cells. Mechanistic analysis supports a regulatory model, in which hypoxia-induced H3K36me3 mark recruits DNMT3A to demethylate CpG in the hypoxia-responsive element (HRE), thereby facilitating HIF-1α binding and TWIST1 activation. This study demonstrates for the first time an in vivo functional role of the active DNA demethylation activity of DNMT3A and its potential as a novel therapeutic target of anti-cancer development.