Canonical WNT signaling-dependent gating of MYC requires a noncanonical CTCF function at a distal binding site

Gene-gating of a MYC oncogenic super-enhancer (OSE) increases its expression in colon cancer cells in a poorly understood process. Here the authors show that MYC gating requires a CTCF binding site (CTCFBS) within the OSE that directs the stepwise trafficking of the OSE to the nuclear pore to facilitate increased nuclear export of MYC mRNA, which results in a growth advantage. Abnormal WNT signaling increases MYC expression in colon cancer cells in part via oncogenic super-enhancer-(OSE)-mediated gating of the active MYC to the nuclear pore in a poorly understood process. We show here that the principal tenet of the WNT-regulated MYC gating, facilitating nuclear export of the MYC mRNA, is regulated by a CTCF binding site (CTCFBS) within the OSE to confer growth advantage in HCT-116 cells. To achieve this, the CTCFBS directs the WNT-dependent trafficking of the OSE to the nuclear pore from intra-nucleoplasmic positions in a stepwise manner. Once the OSE reaches a peripheral position, which is triggered by a CTCFBS-mediated CCAT1 eRNA activation, its final stretch (<= 0.7 mu m) to the nuclear pore requires the recruitment of AHCTF1, a key nucleoporin, to the CTCFBS. Thus, a WNT/ss-catenin-AHCTF1-CTCF-eRNA circuit enables the OSE to promote pathological cell growth by coordinating the trafficking of the active MYC gene within the 3D nuclear architecture.

Automated summary

The gene gating of MYC oncogenic super-enhancer plays an important role in colon cancer cells, but its mechanism is poorly understood. This study reveals that WNT signaling increases MYC expression in colon cancer cells by facilitating nuclear export of MYC mRNA through the regulation of CTCF binding site within the oncogenic super-enhancer. Furthermore, it is found that the trafficking of the oncogenic super-enhancer to the nuclear pore is essential for the growth advantage of cancer cells.