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

Abstract

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.

Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer

“…While being relatively important in normal cells, this process is essential for cancer cells, highlighting a potential tumor-specific metabolic target. Furthermore, the main target of SIRT5 is glutamate dehydrogenase 1 (GLUD1), which is also an important regulator of redox homeostasis; this is consistent with the previously described protective effect of SIRT5 against cellular oxidative stress [54]. Li et al found that Glutaminase 1 (GLS1), both the known isoforms, kidney-type glutaminase (KGA) and glutaminase C (GAC), is highly expressed in HCC, and that targeting GLS1 reduces the expression of stemness-related genes and cancer stem cells properties in vitro.…”

“…Antioxidant enzyme with mitochondrial localization, member of the thioredoxin system BC [111] HCC [112] MESO [113] EC [114] PC [115] SIRT1 NAD + -dependent protein deacetylase, plays key roles in DNA damage response and metabolic adaptation to energy stress. Along with PGC1α, is involved in chemotherapy-induced shift to OXPHOS in CRC cells CRC [47,116] SIRT5 NAD-dependent protein lysine demalonylase, desuccinylase and deglutarylase able to remove malonyl, succinyl, and glutaryl groups from the lysine residues of proteins CRC [54] Hexokinase II (HK2)…”

Associations of sirtuins with clinicopathological variables and prognosis in human ovarian cancer

“…SIRT5 has been reported to possess dual roles in the regulation of various types of carcinoma, suggesting that SIRT5 acts as a tumor suppressor in hepatic cancer by inhibiting acyl-CoA oxidase 1 (42). However, SIRT5 has also been demonstrated to function as an oncogene in the carcinogenesis of colorectal cancer (CRC), potentially by stimulating glutamine metabolism through the activation of dehydrogenase 1 during the tricarboxylic-acid cycle in CRC cells (43). The fact that SIRT5 exhibits dual effects on the regression of different tumors may depend on the dominant factor in the microenvironment and the signaling pathway.…”

Integrative Analysis of Sirtuins and Their Prognostic Significance in Clear Cell Renal Cell Carcinoma

“…SIRT5 was overexpressed in non-small cell lung cancer and colorectal cancer, high SIRT5 expression was an unfavorable predictor of survival. Overexpression of SIRT5 promoted cancer cell growth and drug resistance (34,35). SIRT5 was recently reported to be down-regulated in glioblastoma and its down-regulation was associated with poor prognosis (35,36).…”