| Literature DB >> 31185214 |
Meng Li1, Ying-Ling Chiang2, Costas A Lyssiotis3, Matthew R Teater1, Jun Young Hong2, Hao Shen1, Ling Wang1, Jing Hu2, Hui Jing2, Zhengming Chen4, Neeraj Jain5, Cihangir Duy1, Sucharita J Mistry1, Leandro Cerchietti1, Justin R Cross6, Lewis C Cantley7, Michael R Green5, Hening Lin8, Ari M Melnick9.
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.Entities:
Keywords: DLBCL; GDH; SIRT3; TCA cycle; YC8-02 inhibitor; autophagy; cancer metabolism; glutaminolysis
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Year: 2019 PMID： 31185214 PMCID： PMC7534582 DOI： 10.1016/j.ccell.2019.05.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743