Fig. 7. A model outlining the role of the CTCFBS to effectuate the WNT-controlled stepwise trafficking of MYC to the nuclear pore.

The migration of the OSE to the nuclear periphery/pore is postulated to occur in three phases: one initially random movement of the OSE in the nuclear interior is followed by a preferential localization of the OSE to a position close to the periphery. This process correlates with WNT-induced activation of CCAT1 transcription, mediated by the CTCFBS potentially in collaboration with the flanking TCF4 motifs. A third key event is the recruitment of AHCTF1 to the CTCF-complexed OSE, which likely occurs close to the periphery in positions illustrated by proximities between CTCF and AHCTF1. Importantly, this last step is critical for the ability of the OSE to reach the nuclear pore. Prior to the anchoring of MYC to the nuclear pore, the potential for direct interaction between the OSE and MYC is highest within 0.5 μm from the nuclear pore, paralleled by declining CCAT1 transcription. This entire process is strongly reduced or absent in mutant D3/E4 HCT-116 cells or normal human primary colon epithelial cells in which the region corresponding to the OSE is unable to efficiently bind CTCF.