SETD7 Controls Intestinal Regeneration and Tumorigenesis by Regulating Wnt/β-Catenin and Hippo/YAP Signaling

Dev Cell. 2016 Apr 4;37(1):47-57. doi: 10.1016/j.devcel.2016.03.002.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Axin Protein / genetics
  • Caco-2 Cells
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / pathology*
  • HEK293 Cells
  • Humans
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / pathology*
  • Intestines / pathology
  • MCF-7 Cells
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Methyltransferases / genetics
  • Protein Methyltransferases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Wnt Proteins / genetics*
  • Wnt Signaling Pathway / physiology
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Axin Protein
  • Axin1 protein, mouse
  • Cell Cycle Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • Wnt Proteins
  • Yap protein, mouse
  • beta Catenin
  • Protein Methyltransferases
  • Setd7 protein, mouse