作者
Li-Shu Chen,Qing-Hui Qi,Xiaoqing Jiang,Jinliang Wu,Yuanyuan Li,Zhaodan Liu,Yingna Cai,Haowen Ran,S Zhang,Cheng Zhang,Huiran Wu,Shengli Cao,Lanjuan Mi,Dake Xiao,Haohao Huang,Shuai Jiang,Jiaqi Wu,Bohan Li,Jiong Xie,Ji Qi,Fangye Li,Panpan Liang,Haixu Qin,Min Wu,Wenchao Zhou,Chenhui Wang,Weina Zhang,Xin Jiang,Kun Zhang,Hui-Yan Li,X. Zhang,Ailing Li,Tao Zhou,Jianghong Man
摘要
Glioblastoma (GBM) exhibits profound metabolic plasticity for survival and therapeutic resistance, while the underlying mechanisms remain unclear. Here, we show that GBM stem cells (GSCs) reprogram the epigenetic landscape by producing substantial amounts of phosphocreatine (PCr). This production is attributed to the elevated transcription of brain-type creatine kinase (CKB), mediated by Zinc finger E-box binding homeobox 1 (ZEB1). PCr inhibits the poly-ubiquitination of the chromatin regulator bromodomain containing protein 2 (BRD2) by outcompeting the E3 ubiquitin ligase SPOP for BRD2 binding. Pharmacological disruption of PCr biosynthesis by cyclocreatine leads to BRD2 degradation and a decrease in its targets' transcription, which inhibits chromosome segregation and cell proliferation. Notably, cyclocreatine treatment significantly impedes tumor growth and sensitizes tumors to a BRD2 inhibitor in mouse GBM models without detectable side effects. These findings highlight that high production of PCr is a druggable metabolic feature of GBM and a promising therapeutic target for GBM treatment.