Hypoxia-induced CTCF promotes EMT in breast cancer

Cancer cells experiencing hypoxic stress employ epithelial-mesenchymal transition (EMT) to undergo metastasis through rewiring of the chromatin landscape, epigenetics and, importantly, alternative splicing. Here, we showed that hypoxia modulates epigenetic landscape on CTCF promoter that upregulates its expression. Hypoxia driven epigenetic alteration, specifically DNA-demethylation mediated by TET2 is a prerequisite for CTCF induction. Mechanistically, in hypoxic conditions, HIF1α binds to the unmethylated CTCF promoter, causing transcriptional upregulation. Further, we uncover the pivotal role of CTCF in promoting EMT as loss of CTCF abrogated invasiveness of hypoxic breast cancer cells. These results validate the functional contribution of the HIF1α-CTCF axis in promoting EMT in hypoxic breast cancer cells. Lastly, CTCF expression is alleviated and the potential for EMT is diminished when the HIF1α binding is particularly disrupted through the dCas9-DNMT3A system mediated maintenance of DNA-methylation on the CTCF promoter. This may offer a unique therapeutic target in breast cancer.