SIRT2-Mediated Deacetylation and Tetramerization of Pyruvate Kinase Directs Glycolysis and Tumor Growth

Cancer Research
Seong-Hoon ParkDavid Gius

Abstract

Sirtuins participate in sensing nutrient availability and directing metabolic activity to match energy needs with energy production and consumption. However, the pivotal targets for sirtuins in cancer are mainly unknown. In this study, we identify the M2 isoform of pyruvate kinase (PKM2) as a critical target of the sirtuin SIRT2 implicated in cancer. PKM2 directs the synthesis of pyruvate and acetyl-CoA, the latter of which is transported to mitochondria for use in the Krebs cycle to generate ATP. Enabled by a shotgun mass spectrometry analysis founded on tissue culture models, we identified a candidate SIRT2 deacetylation target at PKM2 lysine 305 (K305). Biochemical experiments including site-directed mutants that mimicked constitutive acetylation suggested that acetylation reduced PKM2 activity by preventing tetramerization to the active enzymatic form. Notably, ectopic overexpression of a deacetylated PKM2 mutant in Sirt2-deficient mammary tumor cells altered glucose metabolism and inhibited malignant growth. Taken together, our results argued that loss of SIRT2 function in cancer cells reprograms their glycolytic metabolism via PKM2 regulation, partially explaining the tumor-permissive phenotype of mice lacking Sirt2 Cance...Continue Reading

References

Mar 1, 2005·Cell·Leonard Guarente, Frédéric Picard
May 17, 2005·Mechanisms of Ageing and Development·David A Sinclair
Nov 10, 2005·Journal of the American Chemical Society·Detcho A StoyanovskyValerian E Kagan
Jan 1, 1935·The Biochemical Journal·N U Meldrum, H L Tarr
Aug 17, 2006·Antioxidants & Redox Signaling·David Gius, Douglas R Spitz
Feb 6, 2008·Cell Metabolism·Bjoern Schwer, Eric Verdin
Mar 28, 2008·The Biochemical Journal·William C HallowsJohn M Denu
Jul 8, 2008·Trends in Biochemical Sciences·Emily C Ferguson, Jeffrey C Rathmell
Oct 15, 2008·Molecular Cell·Rui-Hong WangChu-Xia Deng
Jul 31, 2009·Nature·Toren FinkelRaul Mostoslavsky
Mar 7, 1927·The Journal of General Physiology·O WarburgE Negelein
Feb 17, 2010·The International Journal of Biochemistry & Cell Biology·Sybille Mazurek
Aug 28, 2010·Science·Joseph A BaurEric Verdin
Nov 18, 2010·Journal of Cell Science·Karin M RothgiesserMichael O Hottiger
Nov 30, 2011·Current Opinion in Oncology·Jean-Pierre Bayley, Peter Devilee
Jan 4, 2012·Molecular Reproduction and Development·Bethany K RedelRandall S Prather
May 26, 2012·Trends in Biochemical Sciences·Barbara Chaneton, Eyal Gottlieb
Jul 25, 2012·Trends in Endocrinology and Metabolism : TEM·Weibo Luo, Gregg L Semenza
Jul 31, 2013·Proceedings of the National Academy of Sciences of the United States of America·Hui ZhangDavid S Yu
Sep 10, 2013·Cell Cycle·Weiwei Yang, Zhimin Lu
Nov 21, 2013·Antioxidants & Redox Signaling·Athanassios VassilopoulosDavid Gius
Jan 9, 2014·Nature Medicine·Leonard Guarente
Aug 26, 2014·Free Radical Biology & Medicine·Ozkan OzdenDavid Gius

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Citations

Jun 30, 2019·Cell Cycle·Luis Filipe Costa-Machado, Pablo J Fernandez-Marcos
Aug 3, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Juan LiFeiruo Huang
Mar 7, 2020·The Journal of Clinical Investigation·Manchao ZhangFen Xia
Apr 25, 2018·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Norio KudoMinoru Yoshida
Apr 21, 2017·The Journal of Biological Chemistry·Casey L KohnhorstSongon An
Nov 30, 2018·The Journal of Biological Chemistry·Ewa M KosciuczukLeonidas C Platanias
Nov 2, 2019·International Journal of Molecular Sciences·Catalina Carrasco-PozoVicky M Avery
Feb 23, 2018·Frontiers in Oncology·Gopinath PrakasamSybille Mazurek
Sep 16, 2018·International Journal of Molecular Sciences·Xianfeng WangVidula Vachharajani
Sep 16, 2020·International Journal of Molecular Sciences·Kah Ni TanCatalina Carrasco-Pozo
Aug 25, 2018·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Yuxin YangDongdong Lu
Jul 8, 2020·Journal of Experimental & Clinical Cancer Research : CR·Jiao FengChuanyong Guo
Dec 21, 2016·Frontiers in Pharmacology·Zhijie XuZhicheng Gong
Jul 18, 2020·The Journal of Investigative Dermatology·Lihua HaoByung-Hyun Park
Sep 11, 2019·Ageing Research Reviews·Yan WangLili Cui
Jan 10, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Savvas PetanidisKonstantinos Zarogoulidis
Oct 30, 2020·Frontiers in Cell and Developmental Biology·Guo LiWei-Guo Zhu
Mar 16, 2019·Current Opinion in Chemical Biology·Tatsiana KosciukHening Lin
Apr 10, 2021·Nucleic Acids Research·Qiutao XuDao-Xiu Zhou
Mar 17, 2021·Chembiochem : a European Journal of Chemical Biology·Erin Q JenningsJames J Galligan
Jul 9, 2021·Life Sciences·Shahab Shahgaldi, Fatemeh Rezaei Kahmini
Jul 27, 2021·Journal of Cellular Physiology·Yoon-Beom LeeJae-Bong Park
Aug 23, 2019·ACS Chemical Biology·Nicole A SpiegelmanHening Lin
Jan 31, 2017·Journal of Medicinal Chemistry·Sandeep SundriyalMatthew J Fuchter

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