C/EBP beta mediates NQO1 and GSTP1 anti-oxidative reductases expression in glioblastoma, promoting brain tumor proliferation

• Type of Material: Article
• Authors: Kecheng Lei, Emory University; Yiyuan Xia, Emory University; Xiao-Chuan Wang, Huazhong University of Science & Technology; Eun Hee Ahn, Emory University; Lingjing Jin, Tongji University; Keqiang Ye, Emory University
• Language: English
• Date: 2020-07-01
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors. Published by Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.redox.2020.101578
• Title of Journal or Parent Work: Redox Biology
• Volume: 34
• Start Page: 101578
• End Page: 101578
• Grant/Funding Information: This work is funded with Federal funds from National Cancer Institute (NCI), National Institutes of Health (NIH) NIH grant RO1 CA186918 (K.Y.).; Dr. Kecheng Lei was supported by a grant from China Postdoctoral Science Foundation (2018M632168).
• Keywords: Biochemistry & Molecular Biology; GSTP1; Risk; GBM; Transcription factor; Oxidative stress; NQO1; Growth; Gene; Activation; Science & Technology; C/EBP beta; Nuclear factor; C609T Polymorphism; Hydrogen peroxide; Binding protein beta; Cancer; Life Sciences & Biomedicine
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology; Health Sciences, Oncology; Biology, Physiology

Abstract

Glioblastoma (GBM) is the most common and most aggressive brain tumor, associated with high levels of reactive oxidative species (ROS) due to metabolic and signaling aberrations. High ROS levels are detrimental to cells, but it remains incompletely understood how cancer cells cope with the adverse effects. Here we show that C/EBPβ, a ROS responsive transcription factor, regulates the transcription of NQO1 and GSTP1, two antioxidative reductases, which neutralize ROS in the GBM and mediates their proliferation. C/EBPβ is upregulated in EGFR overexpressed GBM cells, inversely correlated with the survival rates of brain tumor patients. Interestingly, C/EBPβ binds the promoters of NQO1 and GSTP1 and escalates their expression. Overexpression of C/EBPβ selectively decreases the ROS in EGFR-overexpressed U87MG cells and promotes cell proliferation via upregulating NQO1 and GSTP1; whereas knocking down C/EBPβ elevates the ROS and reduces proliferation by repressing the reductases. Accordingly, C/EBPβ mediates the brain tumor growth in vivo, coupling with NQO1 and GSTP1 expression and ROS levels. Hence, C/EBPβ regulates the expression of antioxidative reductases and balances the ROS, promoting brain tumor proliferation.