SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis
SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis
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DOI：
10.1073/pnas.1911954116
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发表时间：
2019-12-26
影响因子：
11.1
通讯作者：
Cerione, Richard A.
中科院分区：
文献类型：
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作者：
Greene, Kai Su;Lukey, Michael J.;Cerione, Richard A.
线粒体酶谷氨酰胺酶（GLS）在肿瘤发生过程中经常上调，并被评估为癌症治疗的靶点。GLS催化谷氨酰胺水解为谷氨酸盐，然后为不同的代谢途径提供碳和/或氮。在这里，我们报告SIRT 5，线粒体NAD（+）依赖性赖氨酸脱酰酶，在稳定GLS中起着关键作用。在转化细胞中，SIRT 5通过使GLS去琥珀酰化从而保护其免受泛素介导的降解来调节谷氨酰胺代谢。此外，我们发现SIRT 5在细胞转化过程中上调，并支持增殖和肿瘤发生。人乳腺肿瘤中SIRT 5表达升高与患者预后不良相关。这些发现揭示了增加癌细胞中GLS表达的机制，并确立了SIRT 5在代谢重编程和乳腺肿瘤发生中的作用。
The mitochondrial enzyme glutaminase (GLS) is frequently upregulated 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.