Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis.

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.

• Authors: Meng Li, Ying-Ling Chiang, Costas A Lyssiotis, Matthew R Teater, Jun Young Hong, Hao Shen, Ling Wang, Jing Hu, Hui Jing, Zhengming Chen, Neeraj Jain, Cihangir Duy, Sucharita J Mistry, Leandro Cerchietti, Justin R Cross, Lewis C Cantley, Michael R Green, Hening Lin, Ari M Melnick
• Journal: Cancer cell (Cancer Cell) Vol. 35 Issue 6 Pg. 916-931.e9 (06 10 2019) ISSN: 1878-3686 [Electronic] United States
• PMID: 31185214 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Sirt3 protein, mouse
• Glutamine
• Acetyl Coenzyme A
• SIRT3 protein, human
• Sirtuin 3

Topics

• Acetyl Coenzyme A (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Autophagic Cell Death (drug effects)
• Cell Proliferation (drug effects)
• Citric Acid Cycle (drug effects)
• Energy Metabolism (drug effects)
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Glutamine (metabolism)
• HEK293 Cells
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Lymphoma, Large B-Cell, Diffuse (drug therapy, enzymology, genetics, pathology)
• MCF-7 Cells
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Molecular Targeted Therapy
• Signal Transduction
• Sirtuin 3 (antagonists & inhibitors, deficiency, genetics, metabolism)
• Xenograft Model Antitumor Assays