title: SETD7 Controls Intestinal Regeneration and Tumorigenesis by Regulating Wnt/β-Catenin and Hippo/YAP Signaling.
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.
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: menno.oudhoff@ntnu.no.
authors.forename: Menno J
authors.initials: MJ
authors.lastname: Oudhoff
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Mitchell J S
authors.initials: MJS
authors.lastname: Braam
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Spencer A
authors.initials: SA
authors.lastname: Freeman
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Denise
authors.initials: D
authors.lastname: Wong
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Rattray
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Frann
authors.initials: F
authors.lastname: Antignano
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Snyder
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Ido
authors.initials: I
authors.lastname: Refaeli
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hughes
authors.affiliation: 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.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McNagny
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Gold
authors.affiliation: 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.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Department of Gastroenterology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: 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.
authors.forename: Fabio M V
authors.initials: FMV
authors.lastname: Rossi
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Tatlock
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA.
authors.forename: Dafydd R
authors.initials: DR
authors.lastname: Owen
authors.affiliation: The Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: 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: colby.zaph@monash.edu.
authors.forename: Colby
authors.initials: C
authors.lastname: Zaph
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein / Q000235:genetics; D018938:Caco-2 Cells; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology*; D007422:Intestines / Q000473:pathology; D061986:MCF-7 Cells; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000502:physiology; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; C555452:Axin1 protein, mouse; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051176:beta Catenin; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C562044:Setd7 protein, mouse