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.

Developmental Cell
|April 6, 2016
PubMed

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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