title: SIRT2-Mediated Deacetylation and Tetramerization of Pyruvate Kinase Directs Glycolysis and Tumor Growth.
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 Cancer Res; 76(13); 3802-12. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Ozkan
authors.initials: O
authors.lastname: Ozden
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Laboratory for Molecular Cancer Biology, Robert Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Ha Yong
authors.initials: HY
authors.lastname: Song
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Yueming
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Yufan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Laboratory for Molecular Cancer Biology, Robert Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Medicine, University of Illinois, College of Medicine, Chicago, Illinois.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Principe
authors.affiliation: Department of Radiation Oncology, Norton Cancer Center, Louisville, Kentucky.
authors.forename: Yong-Il
authors.initials: YI
authors.lastname: Cha
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Meejeon
authors.initials: M
authors.lastname: Roh
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Laboratory for Molecular Cancer Biology, Robert Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vassilopoulos
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. david.gius@northwestern.edu.
authors.forename: David
authors.initials: D
authors.lastname: Gius
mesh_terms: D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D056565:Sirtuin 2 / Q000502:physiology*; D013963:Thyroid Hormones / Q000737:chemistry* / Q000378:metabolism*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D005947:Glucose; D008565:Membrane Proteins; D056565:Sirtuin 2; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C418743:Sirt2 protein, mouse