SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis

Greene, K. S., Lukey, M. J., Wang, X., Blank, B., Druso, J. E., Lin, M. J., Stalnecker, C. A., Zhang, C., Negron Abril, Y., Erickson, J. W., Wilson, K. F., Lin, H., Weiss, R. S., Cerione, R. A. (December 2019) SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis. Proc Natl Acad Sci U S A. ISSN 1091-6490 (Public Dataset)

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DOI: 10.1073/pnas.1911954116


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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA silencing
diseases & disorders > cancer > cancer types > breast cancer
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation
organs, tissues, organelles, cell types and functions > organs types and functions > metabolism
CSHL Authors:
Communities: CSHL labs > Lukey lab
Depositing User: Adrian Gomez
Date: 16 December 2019
Date Deposited: 27 Jan 2020 16:35
Last Modified: 27 Jan 2020 16:35
PMCID: PMC6936584
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