机构：[1]Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, China.[2]Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics， Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.四川省人民医院[3]Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026)，Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.四川省人民医院[4]Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Tianjin Institute of Environmental and Operational Medicine, Tianjin, China.[5]Department of Neurosurgery, Beijing Fengtai Hospital, Beiing, China.[6]Department of Neurosurgery, First Medical Center of PL A General Hospital, Beijing, China.[7]Intelligent Pathology Institute, The First Affliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.[8]Department of Laboratory Medicine and Department of Ultrasound, Sichuan Academy of Medical Sciences， Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China四川省人民医院[9]State Key Laboratory of Toxicology and Medical Countermeasures, Bejjing Institute of Pharmacology and Toxicology, Beijing, China.
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.
基金：
We thank Dr. Jeremy Rich (University of Pittsburgh, USA) for kindly providing GSCs,
Dr. Shideng Bao (Cleveland Clinic, USA) for kindly providing NPCs. This research
was supported by grants from the National Key Research and Development Program
of China (2020YFA0707703， 2017YFA0505602)， and National Natural Science
Foundation of China (no.81872408, 81872153).
第一作者机构：[1]Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, China.
共同第一作者：
通讯作者：
通讯机构：[1]Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, China.[*1]Nanhu Laboratory, National Center of Biomedical Analysis, 27 Taiping Road, Haidian District, Beijing
推荐引用方式(GB/T 7714)：
Chen Lishu,Qi Qinghui,Jiang Xiaoqing,et al.Phosphocreatine promotes epigenetic reprogramming to facilitate glioblastoma growth through stabilizing BRD2[J].Cancer Discovery.2024,14(8):1547-1565.doi:10.1158/2159-8290.CD-23-1348.
APA：
Chen Lishu,Qi Qinghui,Jiang Xiaoqing,Wu Jin,Li Yuanyuan...&Man Jianghong.(2024).Phosphocreatine promotes epigenetic reprogramming to facilitate glioblastoma growth through stabilizing BRD2.Cancer Discovery,14,(8)
MLA：
Chen Lishu,et al."Phosphocreatine promotes epigenetic reprogramming to facilitate glioblastoma growth through stabilizing BRD2".Cancer Discovery 14..8(2024):1547-1565
医学