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

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

doi:10.1016/j.devcel.2016.03.002

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.

Authors

Menno J Oudhoff¹, Mitchell J S Braam², Spencer A Freeman³, Denise Wong², David G Rattray², Jia Wang³, Frann Antignano², Kimberly Snyder², Ido Refaeli², Michael R Hughes², Kelly M McNagny⁴, Michael R Gold³, Cheryl H Arrowsmith⁵, Toshiro Sato⁶, Fabio M V Rossi⁴, John H Tatlock⁷, Dafydd R Owen⁸, Peter J Brown⁹, Colby Zaph¹⁰

Affiliations

¹ The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: [email protected].
² The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
³ Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
⁴ The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
⁵ The Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁶ Department of Gastroenterology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
⁷ Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
⁸ Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA.
⁹ The Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
¹⁰ The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Electronic address: [email protected].

PMID: 27046831
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
Histone-Lysine N-Methyltransferase
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
YAP-Signaling Proteins
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-Signaling Proteins
Yap1 protein, mouse
beta Catenin
Protein Methyltransferases
Histone-Lysine N-Methyltransferase
Setd7 protein, mouse