IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low oxoglutarate dehydrogenase expression by disturbingα-ketoglutarate-related metabolism and epigenetic modification  

作　　者：Yuanlin Zhao Ying Yang Risheng Yang Chao Sun Xing Gao Xiwen Gu Yuan Yuan Yating Nie Shenhui Xu Ruili Han Lijun Zhang Jing Li Peizhen Hu Yingmei Wang Huangtao Chen Xiangmei Cao Jing Wu Zhe Wang Yu Gu Jing Ye 

机构地区：[1]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers,Department of Pathology,Xijing Hospital and School of Basic Medicine,Fourth Military Medical University,Xi’an,Shaanxi 710032,China [2]Department of Pathology,Air Force Hospital of Southern Theater Command,Guangzhou,Guangdong 510000,China [3]Department of Neurology,Tangdu Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710038,China [4]Department of Clinical Diagnosis,Tangdu Hospital,Fourth Military Medical University,Xi’an,Shaanxi 710038,China [5]Department of Neurosurgery,the Second Affiliated Hospital of Xi’an Jiaotong University,Xi’an,Shaanxi 710004,China [6]Department of Pathology,School of Basic Medical Sciences,Ningxia Medical University,Yinchuan,Ningxia 750004,China [7]Institute of Analytical Chemistry and Instrument for Life Science,The Key Laboratory of Biomedical Information Engineering of Ministry of Education,School of Life Science and Technology,Xi’an Jiaotong University,Xi’an,Shaanxi 710049,China

出　　处：《Life Metabolism》2024年第2期24-37,共14页生命代谢（英文）

基　　金：supported by funds from the National Key Research and Development Program of China(2022YFA0806501);the National Natural Science Foundation of China(81972342 to J.Y.,82173120 to Y.G.,and 82070298 to L.Z.);the Natural Science Basic Research Plan in ShaanxiProvince(2020JZ-29 to J.Y.).

摘　　要：Isocitrate dehydrogenase(IDH)mutations frequently occur in lower-grade gliomas and secondary glioblastomas.Mutant IDHs exhibit a gain-of-function activity,leading to the production of D-2-hydroxyglutarate(D-2HG)by reducing α-ketoglutarate(α-KG),a central player in metabolism and epigenetic modifications.However,the role ofα-KG homeostasis in IDH-mutated gliomagenesis remains elusive.In this study,we found that low expression of oxoglutarate dehydrogenase(OGDH)was a common feature in IDH-mutated gliomas,as well as inastrocytes.This low expression of OGDH resultedin the accumulation of α-KG and promoted astrocyte maturation.However,IDH1 mutation significantly reducedα-KG levels and increased glutaminolysis and DNA/histone methylation in astrocytes.These metabolic and epigenetic alterations inhibited astrocyte maturation and led to cortical dysplasia in mice.Moreover,our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells,while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation ofα-KG and increasing glutaminolysis.Finally,we found that l-glutamine increasedα-KG levels and augmented the differentiation-promoting effects of AGI5198,an IDH1-mutant inhibitor,in IDH1-mutant glioma cells.Collectively,this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas,providing a potential strategy for the treatment of IDH-mutant gliomas by targetingα-KG homeostasis.

关 键 词：Α-KETOGLUTARATE IDH1 mutation OGDH L-GLUTAMINE gliomas 

分 类 号：R739.4[医药卫生—肿瘤]