title: Loss of SIRT3 Provides Growth Advantage for B Cell Malignancies.
abstract: B cell malignancies comprise a diverse group of cancers that proliferate in lymph nodes, bone marrow, and peripheral blood. SIRT3 (sirtuin 3) is the major deacetylase within the mitochondrial matrix that promotes aerobic metabolism and controls reactive oxygen species (ROS) by deacetylating and activating isocitrate dehydrogenase 2 (IDH2) and superoxide dismutase 2 (SOD2). There is controversy as to whether SIRT3 acts as an oncogene or a tumor suppressor, and here we investigated its role in B cell malignancies. In mantle cell lymphoma patient samples, we found that lower SIRT3 protein expression was associated with worse overall survival. Further, SIRT3 protein expression was reduced in chronic lymphocytic leukemia primary samples and malignant B cell lines compared to primary B cells from healthy donors. This lower level of expression correlated with hyperacetylation of IDH2 and SOD2 mitochondrial proteins, lowered enzymatic activities, and higher ROS levels. Overexpression of SIRT3 decreased proliferation and diminished the Warburg-like phenotype in SIRT3-deficient cell lines, and this effect is largely dependent on deacetylation of IDH2 and SOD2. Lastly, depletion of SIRT3 from malignant B cell lines resulted in greater susceptibility to treatment with an ROS scavenger but did not result in greater sensitivity to inhibition of the hypoxia-inducible factor-1α pathway, suggesting that loss of SIRT3 increases proliferation via ROS-dependent but hypoxia-inducible factor-1α-independent mechanisms. Our study suggests that SIRT3 acts as a tumor suppressor in B cell malignancies, and activating the SIRT3 pathway might represent a novel therapeutic approach for treating B cell malignancies.
authors.affiliation: From the Wisconsin Institute for Discovery and the Department of Biomolecular Chemistry.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: the Medical Scientist Training Program, and the Departments of Medicine and.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Denu
authors.affiliation: From the Wisconsin Institute for Discovery and the Department of Biomolecular Chemistry, the Medical Scientist Training Program, and.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Krautkramer
authors.affiliation: the Departments of Medicine and.
authors.forename: Kreg M
authors.initials: KM
authors.lastname: Grindle
authors.affiliation: Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705 and.
authors.forename: David T
authors.initials: DT
authors.lastname: Yang
authors.affiliation: the Departments of Medicine and the University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53792.
authors.forename: Fotis
authors.initials: F
authors.lastname: Asimakopoulos
authors.affiliation: the Departments of Medicine and the University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53792 pxh@medicine.wisc.edu.
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
authors.affiliation: From the Wisconsin Institute for Discovery and the Department of Biomolecular Chemistry, the University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53792 jmdenu@wisc.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Denu
mesh_terms: D000107:Acetylation; D000368:Aged; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D000099156:Superoxide Dismutase 2
chemical_list: D007521:Isocitrate Dehydrogenase; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D056566:Sirtuin 3; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C538784:IDH2 protein, human; C466093:SIRT3 protein, human
keywords: B cell; ROS; Warburg effect; acetylation; cancer; cell proliferation; isocitrate dehydrogenase; sirtuins; superoxide dismutase (SOD)