1. SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis.
- Author
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Kai Su Greene, Lukey, Michael J., Xueying Wang, Blank, Bryant, Druso, Joseph E., Lin, Miao-chong J., Stalnecker, Clint A., Zhang, Chengliang, Abril, Yashira Negrón, Erickson, Jon W., Wilson, Kristin F., Hening Lin, Weiss, Robert S., and Cerione, Richard A.
- Subjects
NEOPLASTIC cell transformation ,BREAST cancer ,CELL transformation ,CANCER cells ,CANCER treatment - Abstract
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. [ABSTRACT FROM AUTHOR]- Published
- 2019
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