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SETD7 Controls Intestinal Regeneration and Tumorigenesis by Regulating Wnt/β-Catenin and Hippo/YAP Signaling
Menno J Oudhoff1, Mitchell J S Braam1, Spencer A Freeman2
1The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Abstract:
Intestinal tumorigenesis is a result of mutations in signaling pathways that control cellular proliferation, differentiation, and survival. Mutations in the Wnt/β-catenin pathway are associated with the majority of intestinal cancers, while dysregulation of the Hippo/Yes-Associated Protein (YAP) pathway is an emerging regulator of intestinal tumorigenesis. In addition, these closely related pathways play a central role during intestinal regeneration. We have previously shown that methylation of the Hippo transducer YAP by the lysine methyltransferase SETD7 controls its subcellular localization and function. We now show that SETD7 is required for Wnt-driven intestinal tumorigenesis and regeneration. Mechanistically, SETD7 is part of a complex containing YAP, AXIN1, and β-catenin, and SETD7-dependent methylation of YAP facilitates Wnt-induced nuclear accumulation of β-catenin. Collectively, these results define a methyltransferase-dependent regulatory mechanism that links the Wnt/β-catenin and Hippo/YAP pathways during intestinal regeneration and tumorigenesis.
Insights
The enzyme SETD7 is crucial for intestinal cancer growth and regeneration by linking the Wnt/β-catenin and Hippo/Yes-Associated Protein (YAP) pathways. SETD7 methylation of YAP promotes Wnt signaling, driving tumor development.
Area of Science:
- Molecular biology
- Cancer research
- Gastroenterology
Background:
- Intestinal tumorigenesis involves mutations in signaling pathways controlling cell growth and survival.
- Wnt/β-catenin pathway mutations are common in intestinal cancers.
- The Hippo/Yes-Associated Protein (YAP) pathway is an emerging regulator of intestinal tumorigenesis and regeneration.
Purpose of the Study:
- To investigate the role of lysine methyltransferase SETD7 in Wnt-driven intestinal tumorigenesis and regeneration.
- To elucidate the mechanism by which SETD7 links the Wnt/β-catenin and Hippo/YAP pathways.
Main Methods:
- Investigated SETD7's requirement in Wnt-driven intestinal tumorigenesis and regeneration models.
- Analyzed the interaction of SETD7 with YAP, AXIN1, and β-catenin.
- Assessed the effect of SETD7-dependent YAP methylation on β-catenin nuclear accumulation.
Main Results:
- SETD7 is essential for Wnt-driven intestinal tumorigenesis and regeneration.
- SETD7 forms a complex with YAP, AXIN1, and β-catenin.
- SETD7-mediated YAP methylation promotes Wnt-induced nuclear accumulation of β-catenin.
Conclusions:
- SETD7 acts as a methyltransferase linking the Wnt/β-catenin and Hippo/YAP pathways.
- This methyltransferase-dependent mechanism is critical for intestinal regeneration and tumorigenesis.
- Targeting SETD7 may offer a novel therapeutic strategy for intestinal cancers.
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