Huang Shuo, Fantini Damiano, Merrill Bradley J, Bagchi Srilata, Guzman Grace, Raychaudhuri Pradip
Department of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, Chicago, Illinois.
Genome Editing Core, University of Illinois, Chicago, Illinois.
Cancer Res. 2017 Dec 1;77(23):6562-6575. doi: 10.1158/0008-5472.CAN-17-1570. Epub 2017 Oct 11.
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 gene, enabling functional interaction with distant TCF4/β-catenin-binding sites in the intron of 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. .
Wnt/β-连环蛋白信号通路失调驱动结直肠癌的发展，但对该通路的了解仍不完整。在此，我们报告损伤特异性DNA结合蛋白DDB2对β-连环蛋白介导的RNF43激活至关重要，RNF43通过从细胞表面去除Wnt受体来限制Wnt信号传导。在人类增生性结肠病灶中观察到DDB2和RNF43的表达降低。DDB2在该基因的上游位点募集EZH2和β-连环蛋白，从而能够与该基因内含子中远处的TCF4/β-连环蛋白结合位点发生功能性相互作用。DDB2的这种新活性是RNF43作为Wnt信号负反馈调节因子发挥功能所必需的。基因缺失DDB2的小鼠对结肠肿瘤发生的易感性增加，其方式与表达Wnt受体的细胞丰度更高以及下游Wnt通路的更大激活有关。我们的结果确定DDB2既是Wnt信号的伙伴又是调节因子，在抑制结肠癌发展中起重要作用。
