SIRT2 Deacetylates and Inhibits the Peroxidase Activity of Peroxiredoxin-1 to Sensitize Breast Cancer Cells to Oxidant Stress-Inducing Agents.
SIRT2 Deacetylates and Inhibits the Peroxidase Activity of Peroxiredoxin-1 to Sensitize Breast Cancer Cells to Oxidant Stress-Inducing Agents.
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DOI：
10.1158/0008-5472.can-16-0126
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发表时间：
2016-09-15
期刊：
影响因子：
11.2
通讯作者：
Bhalla KN
中科院分区：
文献类型：
--
作者：
Fiskus W;Coothankandaswamy V;Chen J;Ma H;Ha K;Saenz DT;Krieger SS;Mill CP;Sun B;Huang P;Mumm JS;Melnick AM;Bhalla KN
SIRT 2是一种蛋白质脱乙酰酶，在乳腺和肝脏肿瘤中具有肿瘤抑制活性，在那里它发生突变，然而，介导其抗肿瘤活性的关键底物尚未完全确定。在这里，我们证明了SIRT 2结合，脱乙酰化和抑制乳腺癌细胞中的抗氧化蛋白peroxiredoxin（Prdx-1）的过氧化物酶活性。SIRT 2的异位过表达，而不是其催化死亡突变体，增加了由过氧化氢（H2 O2）诱导的细胞内活性氧（ROS）水平，这导致过氧化和多聚体形式的Prdx-1的水平增加，具有分子伴侣活性。SIRT 2水平升高使乳腺癌细胞对氧化应激诱导的细胞内DNA损伤和细胞死亡敏感，这与核FOXO 3A和促凋亡BIM蛋白水平升高有关。此外，SIRT 2水平升高使乳腺癌细胞对三氧化二砷（一种批准的治疗剂）以及其他细胞内ROS诱导剂沿着敏感。相反，反义RNA介导的SIRT 2衰减逆转ROS诱导的毒性，如在斑马鱼胚胎模型系统中所示。总的来说，我们的研究结果表明，SIRT 2的肿瘤抑制活性需要其限制Prdx-1的抗氧化活性的能力，从而使乳腺癌细胞对ROS诱导的DNA损伤和细胞毒性敏感。
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.