SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis

Abstract

The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated during tumorigenesis and is being evaluated as a target for cancer therapy. GLS catalyzes the hydrolysis of glutamine to glutamate, which then supplies diverse metabolic pathways with carbon and/or nitrogen. Here, we report that SIRT5, a mitochondrial NAD+-dependent lysine deacylase, plays a key role in stabilizing GLS. In transformed cells, SIRT5 regulates glutamine metabolism by desuccinylating GLS and thereby protecting it from ubiquitin-mediated degradation. Moreover, we show that SIRT5 is up-regulated during cellular transformation and supports proliferation and tumorigenesis. Elevated SIRT5 expression in human breast tumors correlates with poor patient prognosis. These findings reveal a mechanism for increasing GLS expression in cancer cells and establish a role for SIRT5 in metabolic reprogramming and mammary tumorigenesis.

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

“…Labeling derived from 15 N2-glutamine decreased in one KD A2058 cell line but not the other ( Figure S4C). Overall, these results provide evidence consistent with previous results showing that SIRT5 promotes glutaminase activity (29).…”

“…Similarly, it was recently reported that SIRT5 suppresses apoptosis by deacetylation of cytochrome C, thereby promoting HCC growth (28). SIRT5 also promotes breast cancer tumorigenesis by desuccinylating and stabilizing glutaminase (29), an enzyme that catalyzes the conversion of glutamine to glutamate, which supports the metabolic demands of tumorigenesis (30). In contrast, SIRT5 opposes malignant phenotypes associated with expression of mutant IDH, which generates the novel oncometabolite R-2-hydroxyglutarate, thereby perturbing the epigenome (31).…”

“…In breast cancer cells, SIRT5 desuccinylates GLS to protect it from ubiquitination and subsequent degradation. Loss of SIRT5 resulted in decreased GLS expression, exogenous glutamine consumption, glutamine-derived intracellular metabolite levels, and cellular proliferation (29).…”

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

“…A bunch of mitochondrial proteins have succinylation modification, such as UCP1 in thermogenic function, GLUD1 in glutamate metabolism, SDH in ETC, the TCA cycle, GLS2 and CPS1 in glutaminolysis, ECHA and VLCAD in FAO, HMGCS2 in ketogenesis and SHMT2 in serine catabolism. 229 – 233 SIRT5-mediated desuccinylation also participates in protection against peroxisome-induced oxidative stress via targeting ACOX1. 230 Moreover, SIRT5 functions as a leading regulator of protein malonylation in both cytosolic metabolisms including glycolysis, gluconeogenesis and mitochondria FAO.…”

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…Indeed, SIRT4-KO induces leucine disordered metabolism and leads to glucose intolerance and insulin resistance (Anderson et al, 2017). Meanwhile, elevated SIRT5 expression in breast cancer mediates glutaminase desuccinylation and protects glutaminase from ubiquitin-mediated degradation; this effect has been associated with a poor prognosis in breast cancers (Greene et al, 2019). SIRT3 and SIRT5 also mediate desuccinylation and deacetylation of SHMT2, respectively, suggesting that suppression of serine catabolism might represent a novel strategy to restrain tumor growth (Wei et al, 2018;Yang et al, 2018).…”