ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription
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Kai Li1,*, Bo Gao1,2,*, Jun Li1,*, Haining Chen1,3,*, Yanyan Li1, Yuyan Wei1, Di Gong1, Junping Gao1, Jie Zhang1, Weiwei Tan4, Tianfu Wen5, Le Zhang1, Lugang Huang6, Rong Xiang7, Ping Lin1, Yuquan Wei8
1Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
2Department of Pathology, College of Clinical Medicine, Dali University, Dali, China
3Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
4Department Biorepository, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
5Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
6Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China
7Department of Clinical Medicine, School of Medicine, Nankai University, and Collaborative Innovation Center for Biotherapy, Tianjin, China
8Department of Cancer Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
*These authors have contributed equally to this work
Ping Lin, e-mail: firstname.lastname@example.org
Keywords: sp1-ZNF32-C1QBP axis, oxidative stress, transcriptional regulation, mitochondrial membrane potential, pro-oxidant-based anticancer therapy
Received: June 11, 2015 Accepted: October 06, 2015 Published: October 16, 2015
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.
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