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

Cancer Cell. 2019 Jun 10;35(6):916-931.e9. doi: 10.1016/j.ccell.2019.05.002.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Lymphoma, Large B-Cell, Diffuse / enzymology*
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • MCF-7 Cells
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Molecular Targeted Therapy
  • Signal Transduction
  • Sirtuin 3 / antagonists & inhibitors
  • Sirtuin 3 / deficiency
  • Sirtuin 3 / genetics
  • Sirtuin 3 / metabolism*
  • Xenograft Model Antitumor Assays

Substances

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