SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis

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 S...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 116; no. 52; pp. 26625 - 26632
Main Authors Greene, Kai Su, Lukey, Michael J., Wang, Xueying, Blank, Bryant, Druso, Joseph E., Lin, Miao-chong J., Stalnecker, Clint A., Zhang, Chengliang, Abril, Yashira Negrón, Erickson, Jon W., Wilson, Kristin F., Lin, Hening, Weiss, Robert S., Cerione, Richard A.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 26.12.2019
Subjects
Biological Sciences
Breast cancer
Cancer
Glutaminase
Glutamine
Lysine
Metabolic pathways
Metabolism
Mitochondria
NAD
Transformed cells
Tumorigenesis
Ubiquitin
glutaminase
SIRT5
cancer
metabolism
sirtuin
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Summary: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.
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1K.S.G. and M.J.L. contributed equally to this work.
Edited by Ralph J. DeBerardinis, University of Texas Southwestern Medical Center, Dallas, TX, and accepted by Editorial Board Member Tak W. Mak November 13, 2019 (received for review July 16, 2019)
Author contributions: K.S.G., M.J.L., J.W.E., K.F.W., H.L., R.S.W., and R.A.C. designed research; K.S.G., M.J.L., X.W., B.B., J.E.D., M.-c.J.L., C.A.S., C.Z., Y.N.A., and J.W.E. performed research; K.S.G., M.J.L., and R.A.C. analyzed data; and K.S.G., M.J.L., H.L., R.S.W., and R.A.C. wrote the paper.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1911954116