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-direct 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.

Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer

“…33 However, its role in glycolysis (pro or anti) remains debatable. Seong-Hoon et al found that SIRT2-lacking cells exhibited a higher extent of glycolytic phenotype in mammary tumor cells by targeting PKM2, 34 Young et al found that knockdown of SIRT2 resulted in significantly decreased OXPHOS and increased glycolysis by targeting enolase, GAPDH and aldolase in human fibroblasts. 35 In contrary, Xu et al found that SIRT2 could enhance glycolysis in A549 and MEF cells by targeting PGAM2.…”

SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair

“…For example, SIRT2 deacetylates CDK9, activating its kinase activity in response to DNA replication stress (37). SIRT2 also deacetylates PKM2 and regulates its tetramerization and pyruvate kinase activity, leading to suppression of glycolysis (28). SIRT2 has been reported to deacetylate transcription factor NRF2 and regulate cellular iron homeostasis (70).…”

“…SIRT2 is an NAD + -dependent deacetylase that plays a role in multiple biological processes, such as longevity, lipid and glucose homeostasis, tumor suppression, and neurodegenerative disorders (26)(27)(28)(29)(30). Recent studies revealed the protective action of…”

The Antibiotic Drug Tigecycline: A Focus on its Promising Anticancer Properties

“…Compared with normal cells, cancer cells exhibit markedly upregulated glucose uptake and aerobic glycolysis, increasing the yield of biosynthetic intermediates, providing essential anabolic molecules for cell proliferation and tumor growth (Ribas et al, 2016). Gius’s study suggested that knockdown of sirtuins, a cellular energy sensor, could increase glycolytic metabolism, further promoting mammary tumor growth (Park et al, 2016). Loss of mitochondrial PTEN-induced kinase 1 (PINK1) could promote glioblastoma growth by increasing the Warburg effect in vitro and in vivo (Agnihotri et al, 2016).…”