Hypoxia‑induced genome‑wide DNA demethylation by DNMT3A and EMT of cancer cells

Dr. Shen, Che-Kun James - August, 2025

Epigenetic alterations of DNA methylations and/or histone modifications cause substantial transcriptomic reprogramming in cancer cells during EMT and metastasis, which can be therapeutically targeted by a thorough understanding of the mutual interactions among the epigenetic processes. We have previously discovered that the mammalian DNA methyltransferases (DNMTs) possess redox- and Ca++- dependent active DNA 5mC demethylation activities in addition to the cytosine methylation activity.

In this study, we have carried out experiments using a range of molecular, cellular, and genome editing approaches in conjunction with DNA methylome and DNMT3A ChIP-Seq analyses, We found that active DNA demethylation activity of DNMT3A is essential for hypoxia-induced EMT of the cancer cells, their global genomic DNA demethylation, and promoter DNA demethylation/transcriptional activation of EMT-associated genes. Mechanistic analysis supports a regulatory model where hypoxia-induced H3K36me3 mark recruits DNMT3A to demethylate CpG in the hypoxia-responsive element (HRE), thereby facilitating HIF-1α binding and activation of the promoters of EMT genes.

Altogether, this study has provided the first demonstration of a physiological function of the active DNA demethylation activity of the DNMTs. Equally important, our findings have revealed a missing link between the HIF-1α pathway and the O2-sensing KDM pathway. Finally, the active DNA demethylation activity of DNMT3A has now emerged as a new potential target for therapeutic development to prevent EMT and metastasis of cancer cells.