Xiao Han1, Xianxian Duan2, Zhanzhao Liu2, Yaping Long2, Chang Liu2, Jing Zhou2, Ning Li3, Junfang Qin4, Yue Wang5,6. 1. State Key Laboratory of Medicinal Chemical Biology & College of Pharmacy, Nankai University, Tianjin, 300354, China. 2. School of Medicine, Nankai University, Tianjin, 300071, China. 3. Institute of Disaster Medicine, Tianjin University, Tianjin, 300072, China. 4. School of Medicine, Nankai University, Tianjin, 300071, China. qjf@nankai.edu.cn. 5. School of Medicine, Nankai University, Tianjin, 300071, China. wangyue@nankai.edu.cn. 6. Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Hospital of Stomatology, Nankai University, Tianjin, 300041, China. wangyue@nankai.edu.cn.
Abstract
PURPOSE: Prior studies have noted that zinc finger E-box binding homeobox 1 (ZEB1) is a master transcription regulator, affecting the expression of nearly 2000 genes in breast cancer cells, especially in the epithelial-mesenchymal transition (EMT) process. We now tested the role of ZEB1 on the oxidative stress of cancer cells and explored its possible mechanisms. METHODS: Two human breast cancer cell lines MDA-MB-231 and MCF7 were selected for the ROS test, PCR, immunofluorescence, Western blot, chromatin immunoprecipitation assay, luciferase assay, and enzyme assay. Mouse models experiments and bioinformatics analysis were conducted to test the indicated molecules. RESULTS: We observed ZEB1 could inhibit GPX4 transcription by binding to the E-box motifs and promote breast cancer progression by accumulating intracellular ROS. From the perspective of ROS clearance, Vitamin E enhanced GPX4 function to consume L-glutathione and eliminated excess intracellular ROS. CONCLUSIONS: ZEB1 could not only regulate EMT, but also inhibit GPX4 transcription by binding to the E-box motif. It was important to note that the ZEB1/GPX4 axis had a therapeutic effect on breast cancer metabolism.
PURPOSE: Prior studies have noted that zinc finger E-box binding homeobox 1 (ZEB1) is a master transcription regulator, affecting the expression of nearly 2000 genes in breast cancer cells, especially in the epithelial-mesenchymal transition (EMT) process. We now tested the role of ZEB1 on the oxidative stress of cancer cells and explored its possible mechanisms. METHODS: Two human breast cancer cell lines MDA-MB-231 and MCF7 were selected for the ROS test, PCR, immunofluorescence, Western blot, chromatin immunoprecipitation assay, luciferase assay, and enzyme assay. Mouse models experiments and bioinformatics analysis were conducted to test the indicated molecules. RESULTS: We observed ZEB1 could inhibit GPX4 transcription by binding to the E-box motifs and promote breast cancer progression by accumulating intracellular ROS. From the perspective of ROS clearance, Vitamin E enhanced GPX4 function to consume L-glutathione and eliminated excess intracellular ROS. CONCLUSIONS: ZEB1 could not only regulate EMT, but also inhibit GPX4 transcription by binding to the E-box motif. It was important to note that the ZEB1/GPX4 axis had a therapeutic effect on breast cancer metabolism.
Authors: Angela M Krebs; Julia Mitschke; María Lasierra Losada; Otto Schmalhofer; Melanie Boerries; Hauke Busch; Martin Boettcher; Dimitrios Mougiakakos; Wilfried Reichardt; Peter Bronsert; Valerie G Brunton; Christian Pilarsky; Thomas H Winkler; Simone Brabletz; Marc P Stemmler; Thomas Brabletz Journal: Nat Cell Biol Date: 2017-04-17 Impact factor: 28.824