DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer

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 signali...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2017-12, Vol.77 (23), p.6562-6575
Main Authors: Huang, Shuo, Fantini, Damiano, Merrill, Bradley J, Bagchi, Srilata, Guzman, Grace, Raychaudhuri, Pradip
Format: Article
Language:English
Subjects:
Activation
Animals
beta Catenin - metabolism
Cell Line, Tumor
Cell surface
Colon
Colon cancer
Colonic Neoplasms - genetics
Colonic Neoplasms - pathology
Colorectal cancer
Colorectal carcinoma
Deregulation
Disease Models, Animal
DNA damage
DNA-binding protein
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Enhancer of Zeste Homolog 2 Protein - metabolism
Enzyme Activation
HCT116 Cells
Heparan sulfate
HT29 Cells
Humans
Male
Mice
Mice, Knockout
Negative feedback
Oncogene Proteins - metabolism
Receptors, Wnt - metabolism
RNA Interference
RNA, Small Interfering - genetics
Signal transduction
Wnt protein
Wnt Signaling Pathway - genetics
β-Catenin
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Summary: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. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-17-1570