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Supplementary Figures S1-S5 from DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer

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posted on 2023-03-31, 01:06 authored by Shuo Huang, Damiano Fantini, Bradley J. Merrill, Srilata Bagchi, Grace Guzman, Pradip Raychaudhuri

Figure S1: DDB2 is required for the activation of Rnf43 mRNA expression (Related to Figure 1). Figure S2: mRNA expression of RNF43 decreases from Grade 2 to Grade 3 in human patient colon adenocarcinoma samples. Figure S3: DDB2 specifically binds with P2 region on Rnf43 regulatory region. Figure S4: CRISPR/Cas9 system was used to deleted DDB2 binding site on RNF43 upstream regulatory region (Related to Figure 2). Figure S5: HT-29 cells with deleted DDB2 binding motif showed decreased protein expression of RNF43 (Related to Figure 2).

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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.