SIRT3-Mediated Dimerization of IDH2 Directs Cancer Cell Metabolism and Tumor Growth.
SIRT3-Mediated Dimerization of IDH2 Directs Cancer Cell Metabolism and Tumor Growth.
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DOI：
10.1158/0008-5472.can-16-2393
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发表时间：
2017-08-01
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：
Zou X;Zhu Y;Park SH;Liu G;O'Brien J;Jiang H;Gius D
异柠檬酸脱氢酶IDH2通过氧化异柠檬酸产生α-酮戊二酸，将葡萄糖代谢与氧化磷酸化联系起来。在这项研究中，我们报告了SIRT3的缺失增加了IDH2在赖氨酸413位的乙酰化(IDH2-K413-Ac)，从而通过减少IDH2二聚体的形成而降低了其酶活性。在癌细胞中表达基因乙酰化模拟IDH2突变体(IDH2K413Q)可降低IDH2二聚化和酶活性，增加细胞内活性氧(ROS)和糖酵解，提示线粒体代谢发生变化。同时，IDH2 K413Q的过表达促进了裸鼠的细胞转化和肿瘤形成，导致了肿瘤允许的表型。免疫组织化学染色显示，IDH2乙酰化水平在高危肠腔B患者中高于低危肠腔A患者。总体而言，这些结果表明SIRT3酶活性、IDH2-K413乙酰化决定的二聚化和癌症允许表型之间存在潜在的关系。
The isocitrate dehydrogenase IDH2 produces α-ketoglutarate by oxidizing isocitrate, linking glucose metabolism to oxidative phosphorylation. In this study, we report that loss of SIRT3 increases acetylation of IDH2 at lysine 413 (IDH2-K413-Ac), thereby decreasing its enzymatic activity by reducing IDH2 dimer formation. Expressing a genetic acetylation mimetic IDH2 mutant (IDH2K413Q) in cancer cells decreased IDH2 dimerization and enzymatic activity and increased cellular reactive oxygen species (ROS) and glycolysis, suggesting a shift in mitochondrial metabolism. Concurrently, overexpression of IDH2K413Q promoted cell transformation and tumorigenesis in nude mice, resulting in a tumor-permissive phenotype. Immunohistochemical staining showed that IDH2 acetylation was elevated in high-risk luminal B patients relative to low-risk luminal A patients. Overall, these results suggest a potential relationship between SIRT3 enzymatic activity, IDH2-K413 acetylation-determined dimerization, and a cancer-permissive phenotype.