Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer
- Nicolas Reynoird1,2,11,
- Pawel K. Mazur3,4,11,
- Timo Stellfeld5,
- Natasha M. Flores3,4,
- Shane M. Lofgren6,7,
- Scott M. Carlson1,
- Elisabeth Brambilla2,
- Pierre Hainaut2,
- Ewa B. Kaznowska8,
- Cheryl H. Arrowsmith9,10,
- Purvesh Khatri6,7,
- Carlo Stresemann5,
- Or Gozani1 and
- Julien Sage3,4
- 1Department of Biology, Stanford University, Stanford, California 94305, USA;
- 2Institut 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;
- 3Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA;
- 4Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
- 5Global Drug Discovery, Bayer Pharma AG, 13353 Berlin, Germany;
- 6Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA;
- 7Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, California 94305, USA;
- 8Faculty of Medicine, Centre for Innovative Research in Medical and Natural Sciences, University of Rzeszów, 35959 Rzeszów, Poland;
- 9Structural Genomics Consortium, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario M5G 2M9, Canada;
- 10Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada
- Corresponding authors: julsage{at}stanford.edu, ogozani{at}stanford.edu
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↵11 These authors contributed equally to this work.
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.275529.115.
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Freely available online through the Genes & Development Open Access option.
- Received December 1, 2015.
- Accepted March 1, 2016.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
