SIRT2-Mediated Deacetylation and Tetramerization of Pyruvate Kinase Directs Glycolysis and Tumor Growth.
SIRT2-Mediated Deacetylation and Tetramerization of Pyruvate Kinase Directs Glycolysis and Tumor Growth.
复制标题
DOI：
10.1158/0008-5472.can-15-2498
复制
发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Gius D
中科院分区：
文献类型：
--
作者：
Park SH;Ozden O;Liu G;Song HY;Zhu Y;Yan Y;Zou X;Kang HJ;Jiang H;Principe DR;Cha YI;Roh M;Vassilopoulos A;Gius D
Sirtuins 参与感知营养物质的可用性并指导代谢活动，以使能量需求与能量产生和消耗相匹配。然而，sirtuins 在癌症中的关键靶点目前尚不清楚。在这项研究中，我们确定丙酮酸激酶 (PKM2) 的 M2 亚型是与癌症有关的 Sirtuin SIRT2 的关键靶标。 PKM2 指导丙酮酸和乙酰辅酶 A 的合成，后者被转运至线粒体，用于三羧酸循环中生成 ATP。通过基于组织培养模型的鸟枪质谱分析，我们在 PKM2 赖氨酸 305 (K305) 处确定了候选 SIRT2 脱乙酰化靶点。包括模仿组成型乙酰化的定点突变体在内的生化实验表明，乙酰化通过阻止四聚化为活性酶形式来降低 PKM2 活性。值得注意的是，Sirt2缺陷型乳腺肿瘤细胞中去乙酰化PKM2突变体的异位过度表达改变了葡萄糖代谢并抑制了恶性生长。综上所述，我们的结果表明，癌细胞中 SIRT2 功能的丧失会通过 PKM2 调节重新编程其糖酵解代谢，部分解释了缺乏 Sirt2 的小鼠的肿瘤允许表型。
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.