Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner.

Autor:	Wang YQ; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China., Wang HL; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China., Xu J; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China., Tan J; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China., Fu LN; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China., Wang JL; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China., Zou TH; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China., Sun DF; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China., Gao QY; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China., Chen YX; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China. yingxuanchen71@sjtu.edu.cn.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China. yingxuanchen71@sjtu.edu.cn.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China. yingxuanchen71@sjtu.edu.cn., Fang JY; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.; State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2018 Feb 07; Vol. 9 (1), pp. 545. Date of Electronic Publication: 2018 Feb 07.
DOI:	10.1038/s41467-018-02951-4
Abstrakt:	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 13 C-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.
Databáze:	MEDLINE
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