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DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer

Shuo Huang1, Damiano Fantini1, Bradley J Merrill1,2

  • 1Department of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, Chicago, Illinois.

Cancer Research
|October 13, 2017
PubMed

Insights

Damage-specific DNA-binding protein 2 (DDB2) is crucial for regulating the Wnt/β-catenin pathway. DDB2 suppresses colon cancer by activating RNF43, a key negative feedback regulator.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The Wnt/β-catenin signaling pathway is frequently deregulated in colorectal cancer.
  • RNF43 acts as a negative regulator of Wnt signaling by internalizing Wnt receptors.
  • The precise role of DDB2 in Wnt signaling and cancer remains incompletely understood.

Purpose of the Study:

  • To investigate the role of DDB2 in regulating Wnt/β-catenin signaling and its implications in colorectal cancer development.
  • To elucidate the mechanism by which DDB2 influences RNF43 expression and function.

Main Methods:

  • Analysis of DDB2 and RNF43 expression in human hyperplastic colonic foci.
  • Investigation of DDB2's interaction with EZH2 and β-catenin at the Rnf43 gene locus.
  • Assessment of colon tumor development in DDB2-deficient mice.

Main Results:

  • Reduced DDB2 and RNF43 expression was found in human hyperplastic colonic tissues.
  • DDB2 facilitates β-catenin-mediated activation of RNF43 transcription through interactions at the Rnf43 gene.
  • DDB2 deficiency in mice led to increased susceptibility to colon tumor development, associated with elevated Wnt signaling.

Conclusions:

  • DDB2 is a novel partner and regulator of the Wnt/β-catenin pathway.
  • DDB2 plays a critical role in suppressing colon cancer development by promoting RNF43-mediated negative feedback.
  • DDB2 represents a potential therapeutic target for colorectal cancer.

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