Abstract
Diffuse large B cell lymphomas (DLBCLs) are genetically heterogeneous and highly proliferative neoplasms derived from germinal center (GC) B cells. Here, we show that DLBCLs are dependent on mitochondrial lysine deacetylase SIRT3 for proliferation, survival, self-renewal, and tumor growth in vivo regardless of disease subtype and genetics. SIRT3 knockout attenuated B cell lymphomagenesis in VavP-Bcl2 mice without affecting normal GC formation. Mechanistically, SIRT3 depletion impaired glutamine flux to the TCA cycle via glutamate dehydrogenase and reduction in acetyl-CoA pools, which in turn induce autophagy and cell death. We developed a mitochondrial-targeted class I sirtuin inhibitor, YC8-02, which phenocopied the effects of SIRT3 depletion and killed DLBCL cells. SIRT3 is thus a metabolic non-oncogene addiction and therapeutic target for DLBCLs.
Keywords:
DLBCL; GDH; SIRT3; TCA cycle; YC8-02 inhibitor; autophagy; cancer metabolism; glutaminolysis.
Copyright © 2019 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetyl Coenzyme A / metabolism
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Animals
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Antineoplastic Agents / pharmacology
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Autophagic Cell Death / drug effects
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Cell Proliferation / drug effects*
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Citric Acid Cycle / drug effects
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Energy Metabolism / drug effects*
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Female
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Glutamine / metabolism
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HEK293 Cells
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Lymphoma, Large B-Cell, Diffuse / drug therapy
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Lymphoma, Large B-Cell, Diffuse / enzymology*
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / pathology
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MCF-7 Cells
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Molecular Targeted Therapy
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Signal Transduction
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Sirtuin 3 / antagonists & inhibitors
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Sirtuin 3 / deficiency
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Sirtuin 3 / genetics
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Sirtuin 3 / metabolism*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Histone Deacetylase Inhibitors
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Sirt3 protein, mouse
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Glutamine
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Acetyl Coenzyme A
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SIRT3 protein, human
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Sirtuin 3