Abstract：
Cancer cells experiencing hypoxic stress employ epithelial-mesenchymal transition (EMT) to undergo metastasis through rewiring of the chromatin landscape, epigenetics, and importantly, gene expression. Here, we showed that hypoxia modulates the epigenetic landscape on CTCF promoter and upregulates its expression. Hypoxia-driven epigenetic regulation, specifically DNA demethylation mediated by TET2, is a prerequisite for CTCF induction. Mechanistically, in hypoxic conditions, Hypoxia-inducible factor 1-alpha (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 findings highlight the functional contribution of 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 axis may offer a unique therapeutic target in breast cancer.
摘要：
经历低氧应激的癌细胞采用上皮-间质转化（EMT）通过染色质景观的重新布线进行转移，表观遗传学,而且重要的是,基因表达。这里,我们发现缺氧调节CTCF启动子上的表观遗传景观并上调其表达。缺氧驱动的表观遗传调控，特别是由TET2介导的DNA去甲基化是CTCF诱导的先决条件。机械上,在缺氧条件下，缺氧诱导因子1-α（HIF1α）与未甲基化的CTCF启动子结合，导致转录上调。Further,我们揭示了CTCF在促进EMT中的关键作用,因为CTCF的丧失消除了缺氧乳腺癌细胞的侵袭性.这些发现强调了HIF1α-CTCF轴在促进缺氧乳腺癌细胞EMT中的功能贡献。最后,当通过dCas9-DNMT3A系统介导的CTCF启动子上的DNA甲基化的维持特别破坏HIF1α结合时，CTCF表达得到缓解，并且EMT的潜力降低。该轴可以在乳腺癌中提供独特的治疗靶标。
