title: Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer.
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.
authors.affiliation: 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;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Reynoird
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Mazur
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, 13353 Berlin, Germany;
authors.forename: Timo
authors.initials: T
authors.lastname: Stellfeld
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Flores
authors.affiliation: 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;
authors.forename: Shane M
authors.initials: SM
authors.lastname: Lofgren
authors.affiliation: Department of Biology, Stanford University, Stanford, California 94305, USA;
authors.forename: Scott M
authors.initials: SM
authors.lastname: Carlson
authors.affiliation: 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;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: 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;
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.affiliation: Faculty of Medicine, Centre for Innovative Research in Medical and Natural Sciences, University of Rzeszów, 35959 Rzeszów, Poland;
authors.forename: Ewa B
authors.initials: EB
authors.lastname: Kaznowska
authors.affiliation: 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.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: 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;
authors.forename: Purvesh
authors.initials: P
authors.lastname: Khatri
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, 13353 Berlin, Germany;
authors.forename: Carlo
authors.initials: C
authors.lastname: Stresemann
authors.affiliation: Department of Biology, Stanford University, Stanford, California 94305, USA;
authors.forename: Or
authors.initials: O
authors.lastname: Gozani
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011495:Histone-Lysine N-Methyltransferase; C512570:Smyd2 protein, mouse; C098416:MAP-kinase-activated kinase 3; D017346:Protein Serine-Threonine Kinases
keywords: MAPKAPK3; Ras; SMYD2; lung adenocarcinoma; lysine methylation; pancreatic cancer