title: SIRT2 Deacetylates and Inhibits the Peroxidase Activity of Peroxiredoxin-1 to Sensitize Breast Cancer Cells to Oxidant Stress-Inducing Agents.
abstract: SIRT2 is a protein deacetylase with tumor suppressor activity in breast and liver tumors where it is mutated; however, the critical substrates mediating its antitumor activity are not fully defined. Here we demonstrate that SIRT2 binds, deacetylates, and inhibits the peroxidase activity of the antioxidant protein peroxiredoxin (Prdx-1) in breast cancer cells. Ectopic overexpression of SIRT2, but not its catalytically dead mutant, increased intracellular levels of reactive oxygen species (ROS) induced by hydrogen peroxide, which led to increased levels of an overoxidized and multimeric form of Prdx-1 with activity as a molecular chaperone. Elevated levels of SIRT2 sensitized breast cancer cells to intracellular DNA damage and cell death induced by oxidative stress, as associated with increased levels of nuclear FOXO3A and the proapoptotic BIM protein. In addition, elevated levels of SIRT2 sensitized breast cancer cells to arsenic trioxide, an approved therapeutic agent, along with other intracellular ROS-inducing agents. Conversely, antisense RNA-mediated attenuation of SIRT2 reversed ROS-induced toxicity as demonstrated in a zebrafish embryo model system. Collectively, our findings suggest that the tumor suppressor activity of SIRT2 requires its ability to restrict the antioxidant activity of Prdx-1, thereby sensitizing breast cancer cells to ROS-induced DNA damage and cell cytotoxicity. Cancer Res; 76(18); 5467-78. ©2016 AACR.
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Warren
authors: W
authors: Fiskus
authors: Hyprocell LLC, Branford, Connecticut.
authors: Veena
authors: V
authors: Coothankandaswamy
authors: Georgia Regents University, Augusta, Georgia.
authors: Jianguang
authors: J
authors: Chen
authors: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors: Hongwei
authors: H
authors: Ma
authors: Department of Molecular Physiology, Baylor College of Medicine, Houston, Texas.
authors: Kyungsoo
authors: K
authors: Ha
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Dyana T
authors: DT
authors: Saenz
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Stephanie S
authors: SS
authors: Krieger
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Christopher P
authors: CP
authors: Mill
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Baohua
authors: B
authors: Sun
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston Texas.
authors: Peng
authors: P
authors: Huang
authors: Wilmer Eye Institute and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.
authors: Jeffrey S
authors: JS
authors: Mumm
authors: Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York.
authors: Ari M
authors: AM
authors: Melnick
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. kbhalla@mdanderson.org.
authors: Kapil N
authors: KN
authors: Bhalla
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D020552:Comet Assay; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D054464:Peroxiredoxins / Q000378:metabolism*; D056565:Sirtuin 2 / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D016877:Oxidants; C515940:PRDX1 protein, human; D054464:Peroxiredoxins; D009195:Peroxidase; C474199:SIRT2 protein, human; D056565:Sirtuin 2