TitleSIRT2 Deacetylates and Inhibits the Peroxidase Activity of Peroxiredoxin-1 to Sensitize Breast Cancer Cells to Oxidant Stress-Inducing Agents.
Publication TypeJournal Article
Year of Publication2016
AuthorsFiskus, Warren, Coothankandaswamy Veena, Chen Jianguang, Ma Hongwei, Ha Kyungsoo, Saenz Dyana T., Krieger Stephanie S., Mill Christopher P., Sun Baohua, Huang Peng, Mumm Jeffrey S., Melnick Ari M., and Bhalla Kapil N.
JournalCancer Res
Volume76
Issue18
Pagination5467-78
Date Published2016 09 15
ISSN1538-7445
KeywordsAnimals, Breast Neoplasms, Cell Line, Tumor, Comet Assay, Electrophoresis, Gel, Two-Dimensional, Female, Humans, Immunoblotting, Immunoprecipitation, Microscopy, Confocal, Oxidants, Oxidative Stress, Peroxidase, Peroxiredoxins, Sirtuin 2, Zebrafish
Abstract

<p>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.</p>

DOI10.1158/0008-5472.CAN-16-0126
Alternate JournalCancer Res
PubMed ID27503926
PubMed Central IDPMC5345574
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
R21 MH083614 / MH / NIMH NIH HHS / United States
R41 TR000945 / TR / NCATS NIH HHS / United States