ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription

// Kai Li 1, * , Bo Gao 1, 2, * , Jun Li 1, * , Haining Chen 1, 3, * , Yanyan Li 1 , Yuyan Wei 1 , Di Gong 1 , Junping Gao 1 , Jie Zhang 1 , Weiwei Tan 4 , Tianfu Wen 5 , Le Zhang 1 , Lugang Huang 6 , Rong Xiang 7 , Ping Lin 1 , Yuquan Wei 8 1 Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China 2 Department of Pathology, College of Clinical Medicine, Dali University, Dali, China 3 Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China 4 Department Biorepository, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China 5 Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China 6 Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China 7 Department of Clinical Medicine, School of Medicine, Nankai University, and Collaborative Innovation Center for Biotherapy, Tianjin, China 8 Department 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 Correspondence to: Ping Lin, e-mail: linping@scu.edu.cn 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 ABSTRACT 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.