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

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

Author information

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

PMID:
26988419
PMCID:
PMC4826394
DOI:
10.1101/gad.275529.115
[Indexed for MEDLINE]
Free PMC Article

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