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

• DOI: 10.1016/j.devcel.2016.03.002
• Publication Date: 2016-04-04T16:26:55Z
• Authors: Menno J. Oudhoff; Mitchell J.S. Braam; Spencer A. Freeman; Denise Wong; David G. Rattray; Jia Wang; Frann Antignano; Kimberly Snyder; Ido Refaeli; Michael R. Hughes; Kelly M. McNagny; Michael R. Gold; Cheryl H. Arrowsmith; Toshiro Sato; Fabio M.V. Rossi; John H. Tatlock; Dafydd R. Owen; Peter J. Brown; Colby Zaph
• Keywords: Mice, Knockout; 0303 health sciences; Cell Cycle Proteins; Histone-Lysine N-Methyltransferase; Phosphoproteins; Methylation; 3. Good health; Intestines; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; HEK293 Cells; Axin Protein; Cell Line, Tumor; Intestinal Neoplasms; MCF-7 Cells; Animals; Humans; RNA Interference; Protein Methyltransferases; Caco-2 Cells; Adaptor Proteins, Signal Transducing

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.