Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

Nicolas Reynoird; Pawel K Mazur; Timo Stellfeld; Natasha M Flores; Shane M Lofgren; Scott M Carlson; Elisabeth Brambilla; Pierre Hainaut; Ewa B Kaznowska; Cheryl H Arrowsmith; Purvesh Khatri; Carlo Stresemann; Or Gozani; Julien Sage

doi:10.1101/gad.275529.115

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

Genes Dev. 2016 Apr 1;30(7):772-85. doi: 10.1101/gad.275529.115. Epub 2016 Mar 17.

Authors

Affiliations

¹ Department of Biology, Stanford University, Stanford, California 94305, USA; Institut Albert Bonniot, U1209, Institut National de la Santé et de la Recherche Médicale, UMR5309, Centre National de la Recherche Scientifique, Université Grenoble-Alpes, F-38700 Grenoble, France;
² Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
³ Global Drug Discovery, Bayer Pharma AG, 13353 Berlin, Germany;
⁴ Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA; Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, California 94305, USA;
⁵ Department of Biology, Stanford University, Stanford, California 94305, USA;
⁶ Institut Albert Bonniot, U1209, Institut National de la Santé et de la Recherche Médicale, UMR5309, Centre National de la Recherche Scientifique, Université Grenoble-Alpes, F-38700 Grenoble, France;
⁷ Faculty of Medicine, Centre for Innovative Research in Medical and Natural Sciences, University of Rzeszów, 35959 Rzeszów, Poland;
⁸ Structural Genomics Consortium, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We found that levels of the lysine methyltransferase SMYD2 (SET and MYND domain 2) are elevated in PDAC and that genetic and pharmacological inhibition of SMYD2 restricts PDAC growth. We further identified the stress response kinase MAPKAPK3 (MK3) as a new physiologic substrate of SMYD2 in PDAC cells. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Finally, we show that inhibition of SMYD2 cooperates with standard chemotherapy to treat PDAC cells and tumors. These findings uncover a pivotal role for SMYD2 in promoting pancreatic cancer.

Keywords: MAPKAPK3; Ras; SMYD2; lung adenocarcinoma; lysine methylation; pancreatic cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Pancreatic Ductal / enzymology*
Cell Proliferation / drug effects
Cell Proliferation / genetics
Disease Models, Animal
Enzyme Activation / drug effects
Enzyme Activation / genetics
Enzyme Inhibitors / pharmacology
HEK293 Cells
Histone-Lysine N-Methyltransferase / antagonists & inhibitors
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism*
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Mice
Mice, Inbred C57BL
Pancreatic Neoplasms / enzymology*
Protein Serine-Threonine Kinases / metabolism
Signal Transduction
Stress, Physiological

Substances

Enzyme Inhibitors
Intracellular Signaling Peptides and Proteins
Histone-Lysine N-Methyltransferase
Smyd2 protein, mouse
MAP-kinase-activated kinase 3
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding