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

Nat Commun. 2022 Jan 11;13(1):204. doi: 10.1038/s41467-021-27868-3.


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 μm) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Binding Sites
  • CCCTC-Binding Factor / genetics*
  • CCCTC-Binding Factor / metabolism
  • Cell Nucleus / metabolism
  • Colon / metabolism
  • Colon / pathology
  • Cytosol / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Enhancer Elements, Genetic
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Neoplastic
  • Genome, Human
  • HCT116 Cells
  • Humans
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Whole Genome Sequencing
  • Wnt Signaling Pathway / genetics*


  • AHCTF1 protein, human
  • CCAT1 long noncoding RNA, human
  • CCCTC-Binding Factor
  • CTCF protein, human
  • DNA-Binding Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Long Noncoding
  • RNA, Messenger
  • Transcription Factors