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Cancer Res. 2016 Jul 1;76(13):3802-12. doi: 10.1158/0008-5472.CAN-15-2498. Epub 2016 Apr 27.

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

Author information

1
Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
2
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.
3
Department of Medicine, University of Illinois, College of Medicine, Chicago, Illinois.
4
Department of Radiation Oncology, Norton Cancer Center, Louisville, Kentucky.
5
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.

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.

PMID:
27197174
PMCID:
PMC4930699
DOI:
10.1158/0008-5472.CAN-15-2498
[Indexed for MEDLINE]
Free PMC Article

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