Chromosome loop control of oncogenic MYC produces a common vulnerability in diverse cancers [HiChIP]. Chromosome loop control of oncogenic MYC produces a common vulnerability in diverse cancers [HiChIP]

The majority of human cancers become highly dependent on a deregulated MYC oncogene, thus identifying a common mechanism underlying MYC regulation could provide valuable targets for therapy. We show here that diverse tumor-specific super-enhancers acquired throughout the 3Mb MYC insulated neighborhood functionally interact with a single conserved site occupied by CTCF protein in the MYC promoter. CRISPR-mediated deletion analysis shows that this common CTCF site is required for super-enhancer looping to the MYC promoter, high MYC expression and rapid cell proliferation in multiple cancers. Targeted methylation of the MYC enhancer anchor by a dCAS9-DNMT3A-3L fusion protein abrogates CTCF binding with consequent loss of MYC expression, suggesting a common vulnerability and a novel approach for therapeutic targeting of aggressive cancers. Overall design: Evaluation of SMC1 loops in human colorectal cancer cell line