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

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

Department of Biochemistry

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83 Citations (Scopus)

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. The Wnt/β-catenin and Hippo/YAP pathways are intimately linked in structure and function. Oudhoff et al. provide evidence that the lysine methyltransferase SETD7 is a central link between these pathways. SETD7-dependent methylation of YAP is required for optimal β-catenin-dependent gene expression. Accordingly, loss of SETD7 attenuates Wnt-dependent intestinal tumorigenesis and regeneration.

Original language	English
Pages (from-to)	47-57
Number of pages	11
Journal	Developmental Cell
Volume	37
Issue number	1
DOIs	https://doi.org/10.1016/j.devcel.2016.03.002
Publication status	Published - 2016 Apr 4

ASJC Scopus subject areas

Molecular Biology
Biochemistry, Genetics and Molecular Biology(all)
Developmental Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.devcel.2016.03.002

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Oudhoff, M. J., Braam, M. J. S., Freeman, S. A., Wong, D., Rattray, D. G., Wang, J., Antignano, F., Snyder, K., Refaeli, I., Hughes, M. R., McNagny, K. M., Gold, M. R., Arrowsmith, C. H., Sato, T., Rossi, F. M. V., Tatlock, J. H., Owen, D. R., Brown, P. J., & Zaph, C. (2016). SETD7 Controls Intestinal Regeneration and Tumorigenesis by Regulating Wnt/β-Catenin and Hippo/YAP Signaling. Developmental Cell, 37(1), 47-57. https://doi.org/10.1016/j.devcel.2016.03.002

Oudhoff, MJ, Braam, MJS, Freeman, SA, Wong, D, Rattray, DG, Wang, J, Antignano, F, Snyder, K, Refaeli, I, Hughes, MR, McNagny, KM, Gold, MR, Arrowsmith, CH, Sato, T, Rossi, FMV, Tatlock, JH, Owen, DR, Brown, PJ & Zaph, C 2016, 'SETD7 Controls Intestinal Regeneration and Tumorigenesis by Regulating Wnt/β-Catenin and Hippo/YAP Signaling', Developmental Cell, vol. 37, no. 1, pp. 47-57. https://doi.org/10.1016/j.devcel.2016.03.002

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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. The Wnt/β-catenin and Hippo/YAP pathways are intimately linked in structure and function. Oudhoff et al. provide evidence that the lysine methyltransferase SETD7 is a central link between these pathways. SETD7-dependent methylation of YAP is required for optimal β-catenin-dependent gene expression. Accordingly, loss of SETD7 attenuates Wnt-dependent intestinal tumorigenesis and regeneration.",

author = "Oudhoff, {Menno J.} and Braam, {Mitchell J.S.} and Freeman, {Spencer A.} and Denise Wong and Rattray, {David G.} and Jia Wang and Frann Antignano and Kimberly Snyder and Ido Refaeli and Hughes, {Michael R.} and McNagny, {Kelly M.} and Gold, {Michael R.} and Arrowsmith, {Cheryl H.} and Toshiro Sato and Rossi, {Fabio M.V.} and Tatlock, {John H.} and Owen, {Dafydd R.} and Brown, {Peter J.} and Colby Zaph",

note = "Funding Information: We would like to thank R. Dhesi, L. Rollins (BRC core), A. Johnson (UBCFlow), M. Williams (UBC AbLab), T. Murakami (BRC Genotyping), I. Barta (BRC Histology), and all members of BRC mouse facility. This work was supported by the Australian National Health and Medical Research Council (to C.Z.), Canadian Institutes of Health Research (to M.R.G., K.M.M., and C.Z.), and a Canada Foundation for Innovation grant (to C.Z.). The development of the mouse strains used in this study was supported by funds from the Leon Judah Blackmore Foundation (to F.M.V.R.). S.A.F. was supported by fellowships from the CIHR and the Michael Smith Foundation for Health Research (MSFHR). M.J.O. is a Banting Fellow and an MSFHR Fellow. F.M.V.R. is a Distinguished Scholar in Residence of the Peter Wall Institute for Advanced Studies. C.Z. is an MSFHR Career Investigator and a veski innovation fellow. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc..",

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doi = "10.1016/j.devcel.2016.03.002",

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T1 - SETD7 Controls Intestinal Regeneration and Tumorigenesis by Regulating Wnt/β-Catenin and Hippo/YAP Signaling

AU - Oudhoff, Menno J.

AU - Braam, Mitchell J.S.

AU - Freeman, Spencer A.

AU - Wong, Denise

AU - Rattray, David G.

AU - Wang, Jia

AU - Antignano, Frann

AU - Snyder, Kimberly

AU - Refaeli, Ido

AU - Hughes, Michael R.

AU - McNagny, Kelly M.

AU - Gold, Michael R.

AU - Arrowsmith, Cheryl H.

AU - Sato, Toshiro

AU - Rossi, Fabio M.V.

AU - Tatlock, John H.

AU - Owen, Dafydd R.

AU - Brown, Peter J.

AU - Zaph, Colby

N1 - Funding Information: We would like to thank R. Dhesi, L. Rollins (BRC core), A. Johnson (UBCFlow), M. Williams (UBC AbLab), T. Murakami (BRC Genotyping), I. Barta (BRC Histology), and all members of BRC mouse facility. This work was supported by the Australian National Health and Medical Research Council (to C.Z.), Canadian Institutes of Health Research (to M.R.G., K.M.M., and C.Z.), and a Canada Foundation for Innovation grant (to C.Z.). The development of the mouse strains used in this study was supported by funds from the Leon Judah Blackmore Foundation (to F.M.V.R.). S.A.F. was supported by fellowships from the CIHR and the Michael Smith Foundation for Health Research (MSFHR). M.J.O. is a Banting Fellow and an MSFHR Fellow. F.M.V.R. is a Distinguished Scholar in Residence of the Peter Wall Institute for Advanced Studies. C.Z. is an MSFHR Career Investigator and a veski innovation fellow. Publisher Copyright: © 2016 Elsevier Inc..

PY - 2016/4/4

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N2 - 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. The Wnt/β-catenin and Hippo/YAP pathways are intimately linked in structure and function. Oudhoff et al. provide evidence that the lysine methyltransferase SETD7 is a central link between these pathways. SETD7-dependent methylation of YAP is required for optimal β-catenin-dependent gene expression. Accordingly, loss of SETD7 attenuates Wnt-dependent intestinal tumorigenesis and regeneration.

AB - 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. The Wnt/β-catenin and Hippo/YAP pathways are intimately linked in structure and function. Oudhoff et al. provide evidence that the lysine methyltransferase SETD7 is a central link between these pathways. SETD7-dependent methylation of YAP is required for optimal β-catenin-dependent gene expression. Accordingly, loss of SETD7 attenuates Wnt-dependent intestinal tumorigenesis and regeneration.

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

Abstract

ASJC Scopus subject areas

UN SDGs

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