ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription.
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.
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Kai
K
Li
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.|Department of Pathology, College of Clinical Medicine, Dali University, Dali, China.
Bo
B
Gao
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Jun
J
Li
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.|Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
Haining
H
Chen
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Yanyan
Y
Li
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Yuyan
Y
Wei
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Di
D
Gong
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Junping
J
Gao
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Jie
J
Zhang
Department Biorepository, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Weiwei
W
Tan
Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
Tianfu
T
Wen
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Le
L
Zhang
Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China.
Lugang
L
Huang
Department of Clinical Medicine, School of Medicine, Nankai University, and Collaborative Innovation Center for Biotherapy, Tianjin, China.
Rong
R
Xiang
Department of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Ping
P
Lin
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.
Yuquan
Y
Wei
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D000975:Antioxidants; C087299:C1QBP protein, human; D002352:Carrier Proteins; D051741:Kruppel-Like Transcription Factors; D024101:Mitochondrial Proteins; D016877:Oxidants; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C111477:ZNF32 protein, human; D048051:p38 Mitogen-Activated Protein Kinases
mitochondrial membrane potential; oxidative stress; pro-oxidant-based anticancer therapy; sp1-ZNF32-C1QBP axis; transcriptional regulation