Abstract
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.
© 2022. The Author(s).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Binding Sites
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CCCTC-Binding Factor / genetics*
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CCCTC-Binding Factor / metabolism
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Cell Nucleus / metabolism
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Colon / metabolism
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Colon / pathology
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Cytosol / metabolism
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Enhancer Elements, Genetic
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Gene Expression Regulation, Neoplastic
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Genome, Human
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HCT116 Cells
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Humans
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Protein Binding
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Proto-Oncogene Proteins c-myc / genetics*
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Long Noncoding / genetics*
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RNA, Long Noncoding / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Whole Genome Sequencing
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Wnt Signaling Pathway / genetics*
Substances
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AHCTF1 protein, human
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CCAT1 long noncoding RNA, human
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CCCTC-Binding Factor
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CTCF protein, human
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DNA-Binding Proteins
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MYC protein, human
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Proto-Oncogene Proteins c-myc
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RNA, Long Noncoding
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RNA, Messenger
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Transcription Factors