TitleNon-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis.
Publication TypeJournal Article
Year of Publication2019
AuthorsLi, Meng, Chiang Ying-Ling, Lyssiotis Costas A., Teater Matthew R., Hong Jun Young, Shen Hao, Wang Ling, Hu Jing, Jing Hui, Chen Zhengming, Jain Neeraj, Duy Cihangir, Mistry Sucharita J., Cerchietti Leandro, Cross Justin R., Cantley Lewis C., Green Michael R., Lin Hening, and Melnick Ari M.
JournalCancer Cell
Volume35
Issue6
Pagination916-931.e9
Date Published2019 06 10
ISSN1878-3686
KeywordsAcetyl Coenzyme A, Animals, Antineoplastic Agents, Autophagic Cell Death, Cell Proliferation, Citric Acid Cycle, Energy Metabolism, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Glutamine, HEK293 Cells, Histone Deacetylase Inhibitors, Humans, Lymphoma, Large B-Cell, Diffuse, MCF-7 Cells, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Molecular Targeted Therapy, Signal Transduction, Sirtuin 3, Xenograft Model Antitumor Assays
Abstract

<p>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.</p>

DOI10.1016/j.ccell.2019.05.002
Alternate JournalCancer Cell
PubMed ID31185214
PubMed Central IDPMC7534582
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States