C/EBPβ mediates NQO1 and GSTP1 anti-oxidative reductases expression in glioblastoma, promoting brain tumor proliferation
Kecheng Lei,
Yiyuan Xia,
Xiao-Chuan Wang,
Eun Hee Ahn,
Lingjing Jin,
Keqiang Ye
Affiliations
Kecheng Lei
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Neurotoxin Research Center of Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Neurological Department of Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
Yiyuan Xia
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
Xiao-Chuan Wang
Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
Eun Hee Ahn
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
Lingjing Jin
Neurotoxin Research Center of Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Neurological Department of Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China; Corresponding authors.
Keqiang Ye
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Corresponding authors.
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.
