Fiskus, W., Coothankandaswamy, V., Chen, J., Ma, H., Ha, K., Saenz, D.T., Krieger, S.S., Mill, C.P., Sun, B., Huang, P., Mumm, J.S., Melnick, A., Bhalla, K.N. (2016) SIRT2 deacetylates and inhibits the peroxidase activity of peroxiredoxin-1 to sensitize breast cancer cells to oxidant stress inducing agents. Cancer research. 76(18):5467-78.
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 anti-oxidant 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 (H2O2), which led to increased levels of an over-oxidized 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 pro-apoptotic BIM protein. Additionally, 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 anti-oxidant activity of Prdx-1, thereby sensitizing breast cancer cells to ROS-induced DNA damage and cell cytotoxicity.