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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. Herein, 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, that phenocopied the effects of SIRT3 depletion and killed DLBCL cells. SIRT3 is thus a metabolic non-oncogene addiction and therapeutic target for DLBCLs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130751 | GEO | 2019/10/08

REPOSITORIES: GEO

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SIRT3 functions in the nucleus in the control of stress-related gene expression.

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2012-10-16 | E-GEOD-41000 | biostudies-arrayexpress

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Project description:Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration, and high fat diet (HFD)-induced metabolic disorders. Thus, we performed a small molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss.

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Analysis of acetylation stoichiometry suggests that SIRT3 repairs nonenzymatic acetylation lesions

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Expression data from mice lacking SIRT3 under dietary stress

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SIRT3 functions in the nucleus in the control of stress-related gene expression.

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