Figure S6: Association of DDB2, TCF4 and β-catenin on Rnf43 upstream region and intron regions.Figure S7: EZH2 and PAF are required for Rnf43 expression.Figure S8: DDB2 is required for the RNF43-mediated sequestration of TCF4 to the nuclear membrane.Figure S9: WES showed missense mutation in Ctnnb1 gene.Figure S10: DDB2 regulates RNF43 and Wnt target gene expression in normal colonic tissues.Figure S11: Model of how DDB2 regulates Wnt pathway and colon cancer development through RNF43.
ARTICLE ABSTRACT
Deregulation of the Wnt/β-catenin signaling pathway drives the development of colorectal cancer, but understanding of this pathway remains incomplete. Here, we report that the damage-specific DNA-binding protein DDB2 is critical for β-catenin–mediated activation of RNF43, which restricts Wnt signaling by removing Wnt receptors from the cell surface. Reduced expression of DDB2 and RNF43 was observed in human hyperplastic colonic foci. DDB2 recruited EZH2 and β-catenin at an upstream site in the Rnf43 gene, enabling functional interaction with distant TCF4/β-catenin–binding sites in the intron of Rnf43. This novel activity of DDB2 was required for RNF43 function as a negative feedback regulator of Wnt signaling. Mice genetically deficient in DDB2 exhibited increased susceptibility to colon tumor development in a manner associated with higher abundance of the Wnt receptor–expressing cells and greater activation of the downstream Wnt pathway. Our results identify DDB2 as both a partner and regulator of Wnt signaling, with an important role in suppressing colon cancer development. Cancer Res; 77(23); 6562–75. ©2017 AACR.
