Cited by 121Sirtuins and Resveratrol in MedicineCancer, Hypoxia, and MetabolismAmino Acid Enzymes and Metabolism

SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma

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Jeong, Seung Min, Lee, Annie, Lee, Jaewon, Haigis, Marcia C.·2014·Journal of Biological Chemistry

Abstract

Glutamine metabolism plays an essential role for growth and proliferation of many cancer cells by providing metabolites for the maintenance of mitochondrial functions and macromolecular synthesis. Aberrant activation of the transcription factor c-Myc, e.g. caused by t(8;14) chromosomal translocation commonly found in Burkitt lymphoma, is a key driver of cellular glutamine metabolism in many tumors, highlighting the need to identify molecular mechanisms that can suppress glutamine usage in these cancers. Recently, the mitochondrial sirtuin SIRT4 has been reported to function as a tumor suppressor by regulating glutamine metabolism, suggesting that it might have therapeutic potential for treating glutamine-dependent cancers. Here, we report that SIRT4 represses Myc-induced B cell lymphomagenesis via inhibition of mitochondrial glutamine metabolism. We found that SIRT4 overexpression can dampen glutamine utilization even in Myc-driven human Burkitt lymphoma cells and inhibit glutamine-dependent proliferation of these cells. Importantly, SIRT4 overexpression sensitizes Burkitt lymphoma cells to glucose depletion and synergizes with pharmacological glycolysis inhibitors to induce cell death. Moreover, SIRT4 loss in a genetic mouse model of Myc-induced Burkitt lymphoma, Eμ-Myc transgenic mouse, greatly accelerates lymphomagenesis and mortality. Indeed, Eμ-Myc-induced B cell lymphoma cells from SIRT4 null mice exhibit increased glutamine uptake and glutamate dehydrogenase activity. Furthermore, we establish that SIRT4 regulates glutamine metabolism independent of Myc. Together, these results highlight the tumor-suppressive role of SIRT4 in Myc-induced B cell lymphoma and suggest that SIRT4 may be a potential target against Myc-induced and/or glutamine-dependent cancers.

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  • SIRT4's overall growth-inhibiting effect results in decreased metabolism and sensitization to glucose inhibition rather than a Warburg-type shift.

    “SIRT4 might also seem to drive a dependence on glucose via its inhibition of fat oxidation and glutamine catabolism, but its overall growth-inhibiting effect results in decreased metabolism and a sensitization to glucose inhibition rather than a Warburg-type shift (Jeong et al, JBC 2014).”

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Authors
Jeong, S. M., Lee, A., Lee, J., & Haigis, M. C.
Affiliations
Harvard University (US)
Corresponding author
Haigis, Marcia C.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2014-02
Volume
289
Issue
7
Pages
4135-4144
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2027930781
Cited by
121
References
27
Citations by year
2026: 1 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 8 · 2021: 13 · 2020: 14 · 2019: 9 · 2018: 16 · 2017: 7 · 2016: 15 · 2015: 14 · 2014: 8
FWCI
5.77
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (R01AG032375)
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
SIRT4, c-Myc, B-cell lymphoma, Burkitt lymphoma, glutamine metabolism, tumor suppressor, mitochondrial metabolism, glutamate dehydrogenase, Eμ-myc transgenic mice, glycolysis inhibitors, glucose depletion, glutamine uptake
MeSH terms
Animals, Burkitt Lymphoma, Female, Glucose, Glutamate Dehydrogenase, Glutamine, Glycolysis, Humans, Male, Models, Genetic, Proto-Oncogene Proteins c-myc, Mice, Knockout, Mitochondrial Proteins, Sirtuins, Cell Line, Tumor, Mice

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