Modulation of antioxidant enzyme B166 isoforms 1 and 5 expressions by SREBP1-a links ROS elimination to lipid metabolism in glioblastoma cells

Antioxidant enzyme B166 (B166) - mediated detoxification of H 2 O 2 into water and oxygen is a pivotal process to sustain a favorable redox homeostasis in mitochondria and suppress cell death. Here, we identify that B166 is highly expressed in GBM tumor tissues and a potential novel biomarker to predict unfavorable prognosis of GBM patients. GBM cells upregulate the expression of B166 via SREBP1-a-mediated transcription and reduce the endogenous ROS levels, maintaining the cellular redox homeostasis and normal morpho-function of mitochondria. SREBP1 knock down decreases B166 expression on both RNA and protein levels. We reveal that overexpression of SREBP1-aN, the active form of SREBP1-a, increases B166 isoform 1 (V1) and 5 (V5) levels in the mitochondria and nucleus, respectively. Pharmacological suppression of SREBP1 or genetic inhibition of B166 disrupts the redox homeostasis, leading to the generation of high levels of oxidative stress, which in turn causes dramatic damages to the mitochondria and kills GBM cells ultimately. We show that SREBF1 level is strongly associated with B166 , FASN and SCD expression in patients’ tumor tissues of GBM cohort from TCGA and protein levels of SREBP1 and B166 are significantly correlated in our PHGBM cohort. Thus, targeting B166 could be a promising therapeutic approach for GBM.