Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner.
Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner.
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Sirtuin5 通过以去谷氨酰化依赖性方式增强谷氨酰胺分解而促进结直肠癌发生。
DOI：
10.1038/s41467-018-02951-4
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发表时间：
2018-02-07
影响因子：
16.6
通讯作者：
Fang JY
中科院分区：
文献类型：
--
作者：
Wang YQ;Wang HL;Xu J;Tan J;Fu LN;Wang JL;Zou TH;Sun DF;Gao QY;Chen YX;Fang JY
可逆的翻译后修饰代表了控制肿瘤代谢的机制。在这里，我们表明，线粒体Sirtuin 5（SIRT 5），介导赖氨酸脱琥珀酰化，脱戊二酰化，脱丙二酰化，发挥作用，在结直肠癌（CRC）谷氨酰胺代谢重新布线。代谢谱分析表明，SIRT 5的缺失导致13 C-谷氨酰胺掺入三羧酸（TCA）循环中间体和谷氨酰胺衍生的非必需氨基酸的显着减少。这减少了快速增长所需的基础。从机制上讲，SIRT 5和谷氨酸脱氢酶1（GLUD 1）之间的直接相互作用导致GLUD 1的脱戊二酰化和功能活化，GLUD 1是细胞谷氨酸解的关键调节因子。一致地，GLUD 1敲低减少了体内和体外SIRT 5诱导的增殖。临床上，SIRT 5的过度表达与CRC的不良预后显著相关。因此，SIRT 5支持谷氨酰胺通过激活GLUD 1回补进入CRC恶性表型中的TCA循环。肿瘤代谢可以通过翻译后修饰来控制。在这里，作者表明Sirtuin 5通过谷氨酸脱氢酶-1促进结肠直肠癌细胞中的谷氨酸氨解，谷氨酸脱氢酶-1是谷氨酸氨解的关键调节剂，诱导其脱戊二酰化和功能活化。
Reversible post-translational modifications represent a mechanism to control tumor metabolism. Here we show that mitochondrial Sirtuin5 (SIRT5), which mediates lysine desuccinylation, deglutarylation, and demalonylation, plays a role in colorectal cancer (CRC) glutamine metabolic rewiring. Metabolic profiling identifies that deletion of SIRT5 causes a marked decrease in 13C-glutamine incorporation into tricarboxylic-acid (TCA) cycle intermediates and glutamine-derived non-essential amino acids. This reduces the building blocks required for rapid growth. Mechanistically, the direct interaction between SIRT5 and glutamate dehydrogenase 1 (GLUD1) causes deglutarylation and functional activation of GLUD1, a critical regulator of cellular glutaminolysis. Consistently, GLUD1 knockdown diminishes SIRT5-induced proliferation, both in vivo and in vitro. Clinically, overexpression of SIRT5 is significantly correlated with poor prognosis in CRC. Thus, SIRT5 supports the anaplerotic entry of glutamine into the TCA cycle in malignant phenotypes of CRC via activating GLUD1. Tumour metabolism can be controlled through post-translational modifications. Here the authors show that Sirtuin5 promotes glutaminolysis in colorectal cancer cells via glutamate dehydrogenase-1, a critical regulator of glutaminolysis, inducing its deglutarylation and functional activation.