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

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.

CTCF: A misguided jack-of-all-trades in cancer cells

“…In colon cancer cells, the binding of CTCF to a distal MYC SE promotes an interaction of the SE with the nucleoporin AHCTF1. In turn, the SE positions the active allele of the MYC oncogene near the nuclear pores, which improves the nuclear export of its transcripts and induces its transcriptional upregulation [116] .…”

Wnt signaling alters CTCF binding patterns and global chromatin structure

“…While a full-time course of CTCF binding upon Wnt activation would be needed to determine the time dynamics of RUWs, β-catenin binding to these sites early (90 minutes or 4 hours; Pagella et al 2023) supports the model in which β-catenin reaches these sites before CTCF. It has previously been reported in the literature that CTCF can bind to or interact with β-catenin 25 , TCF7 54 , and the member of the ChiLS complex LDB1 55 , all of which could thus be considered as potential partners in recruiting CTCF to the chromatin.…”

Senolytics prevent caveolar CaV3.2‐RyR axis malfunction in old vascular smooth muscle

“…The samples were analyzed with a Simple Western assay using the WES™ system (ProteinSimple, Bio‐Techne; Chachoua et al, 2022). The following antibodies were used for the Western analysis: anti‐Ca V 3.2‐rabbit (Alomone Labs, #ACC‐025, diluted 1:5), anti‐rabbit‐caveolin‐1 (Beyotime, #AF1231, diluted 1:5), and anti‐rabbit‐β‐actin (Abcam, #ab115777, diluted 1:150).…”

“…The samples were analyzed with a Simple Western assay using the WES™ system (ProteinSimple, Bio-Techne; Chachoua et al, 2022).…”