GSE202971
DNMT3A-mediated DNA demethylation is required for hypoxia induced EMT of human cancer cells
During epithelial-to-mesenchymal transition (EMT) and metastasis, the cancer cells undergo substantial reprogramming of their transcriptomes, which is closely associated with local/genome-wide changes of DNA methylation and histone modifications. We show that the de novo DNA methyltransferase DNMT3A is required for hypoxia-induced transcription of the EMT gene TWIST1 in different cancer cell lines including the primary colon carcinoma SW480 cells. More extensive studies of the SW480 cells support a regulatory model, in which hypoxia-induced H3K36me3 mark would recruit DNMT3A to demethylate the CpG motif of a hypoxia-responsive element (HRE), thereby facilitating HIF-1a binding to the HRE and transcriptional activation of TWIST1. Methylome analysis indicates that DNMT3A is also required for hypoxia-induced demetylation of a number of other HREs on the SW480 genome. This study demonstrates for the first time an in vivo functional role of the active DNA demethylation activity of DNMT3A in EMT of cancer cells, and consequently its potential for use as therapeutic target of anti-cancer development. Overall design: Compare the genome-wide methylation profile between wild type and DNMT3A-KO SW480 cells under normoxia and hypoxia Run 1 and 2 samples represent the sequencing of the same library.