ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription.
ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription.
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ZNF32 通过调节 C1QBP 转录来防止氧化应激诱导的细胞凋亡。
DOI：
10.18632/oncotarget.5646
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发表时间：
2015-11-10
期刊：
影响因子：
--
通讯作者：
Wei Y
中科院分区：
文献类型：
--
作者：
Li K;Gao B;Li J;Chen H;Li Y;Wei Y;Gong D;Gao J;Zhang J;Tan W;Wen T;Zhang L;Huang L;Xiang R;Lin P;Wei Y
活性氧（ROS）驱动的氧化应激已被认为是一个关键的诱导癌细胞死亡的治疗药物。我们以前的研究已经证明，锌指蛋白（ZNF）32是氧化刺激后细胞存活的关键。然而，ZNF 32介导细胞死亡的机制仍不清楚。在这里，我们表明，在中等水平的ROS，Sp1直接结合到ZNF 32启动子内的两个GC盒激活ZNF 32转录。或者，在细胞毒性ROS浓度下，由于Sp1的结合活性降低，ZNF 32的表达受到抑制。ZNF 32过表达维持线粒体膜电位并增强细胞的抗氧化能力以解毒ROS，并且这些作用促进促氧化剂处理后的细胞存活。或者，ZNF 32缺陷细胞对氧化应激诱导的细胞损伤更敏感和脆弱。从机制上讲，我们证明了补体1 q结合蛋白（C1 QBP）是ZNF 32的直接靶基因，它使p38 MAPK通路失活，从而发挥ZNF 32对氧化应激诱导的细胞凋亡的保护作用。综上所述，我们的研究结果表明Sp1-ZNF 32-C1 QBP轴保护免受氧化应激的新机制，并暗示ZNF 32抑制剂与促氧化剂抗癌药物联合治疗肝细胞癌是一种有前途的策略。
Reactive oxygen species (ROS)-driven oxidative stress has been recognized as a critical inducer of cancer cell death in response to therapeutic agents. Our previous studies have demonstrated that zinc finger protein (ZNF)32 is key to cell survival upon oxidant stimulation. However, the mechanisms by which ZNF32 mediates cell death remain unclear. Here, we show that at moderate levels of ROS, Sp1 directly binds to two GC boxes within the ZNF32 promoter to activate ZNF32 transcription. Alternatively, at cytotoxic ROS concentrations, ZNF32 expression is repressed due to decreased binding activity of Sp1. ZNF32 overexpression maintains mitochondrial membrane potential and enhances the antioxidant capacity of cells to detoxify ROS, and these effects promote cell survival upon pro-oxidant agent treatment. Alternatively, ZNF32-deficient cells are more sensitive and vulnerable to oxidative stress-induced cell injury. Mechanistically, we demonstrate that complement 1q-binding protein (C1QBP) is a direct target gene of ZNF32 that inactivates the p38 MAPK pathway, thereby exerting the protective effects of ZNF32 on oxidative stress-induced apoptosis. Taken together, our findings indicate a novel mechanism by which the Sp1-ZNF32-C1QBP axis protects against oxidative stress and implicate a promising strategy that ZNF32 inhibition combined with pro-oxidant anticancer agents for hepatocellular carcinoma treatment.