Wild-type IDH2 contributes to Epstein-Barr virus-dependent metabolic alterations and tumorigenesis
Wild-type IDH2 contributes to Epstein-Barr virus-dependent metabolic alterations and tumorigenesis
复制标题
野生型 IDH2 有助于 Epstein-Barr 病毒依赖性代谢改变和肿瘤发生
DOI：
10.1016/j.molmet.2020.02.009
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发表时间：
2020
影响因子：
8.1
通讯作者：
Cao Ya
中科院分区：
文献类型：
--
作者：
Shi Feng;He Ya;Li Jiangjiang;Tang Min;Li Yueshuo;Xie Longlong;Zhao Lin;Hu Jianmin;Luo Xiangjian;Zhou Min;Liu Na;Fan Jia;Zhou Jian;Gao Qiang;Qiu ShuangJian;Wu Weizhong;Zhang Xin;Jia Weihua;Bode Ann M.;Cao Ya
EB病毒（Epstein-Barr virus，EBV）是一种公认的致癌病毒，其可以通过靶向重要的代谢酶或调节剂来诱导宿主细胞代谢重编程和肿瘤发生。本研究旨在探讨野生型异柠檬酸脱氢酶2（IDH 2）在EB病毒潜伏膜蛋白1（LMP 1）诱导的代谢重编程和肿瘤发生中的作用。结果IDH 2过表达是头颈部鳞状细胞癌（HNSCC）患者无病生存率较低的预后指标。IDH 2在鼻咽癌（NPC，HNSCC的一种亚型）组织中的表达也上调，其与EBV-LMP 1表达正相关。EBV-LMP 1有助于NPC细胞活力和通过野生型IDH 2介导的异种移植肿瘤生长。胞内α-酮戊二酸（α-KG）和2-羟基戊二酸（2-HG）的IDH 2依赖性变化有助于EBV-LMP 1在体外和体内诱导的肿瘤发生。鼻咽癌患者血清2-HG水平升高与EB病毒DNA和VCA-IgA水平升高有关。血清2-HG水平与鼻咽癌区域淋巴结转移呈显著正相关。EBV-LMP 1增强c-Myc与IDH 2启动子的结合，并通过c-Myc转录激活野生型IDH 2。靶向IDH 2降低细胞内2-HG水平和EBV-LMP 1阳性肿瘤细胞的存活率in vitroandin vivo.ConclusionsOur结果表明，EBV-LMP 1/c-Myc/IDH 2 WT信号转导轴对EBV依赖的代谢变化和肿瘤发生至关重要，这可能为EBV相关癌症的诊断和治疗提供新的见解。
ObjectiveEpstein–Barr virus (EBV) is a well-recognized oncogenic virus that can induce host cell metabolic reprogramming and tumorigenesis by targeting vital metabolic enzymes or regulators. This study aims to explore the role of wild-type isocitrate dehydrogenase 2 (IDH2) in metabolic reprogramming and tumorigenesis induced by EBV-encoded latent membrane protein 1 (LMP1).MethodsMechanistic dissection of wild-type IDH2 in EBV-LMP1-induced tumorigenesis was investigated using western blotting, real-time polymerase chain reaction (PCR), immunochemistry, chromatin immunoprecipitation (ChIP), and luciferase assay. The role of wild-type IDH2 was examined by cell viability assays/Sytox Green stainingin vitroand xenograft assaysin vivo.ResultsIDH2 over-expression is a prognostic indicator of poorer disease-free survival for patients with head and neck squamous cell carcinoma (HNSCC). IDH2 expression is also upregulated in nasopharyngeal carcinoma (NPC, a subtype of HNSCC) tissues, which is positively correlated with EBV-LMP1 expression. EBV-LMP1 contributes to NPC cell viability and xenograft tumor growth mediated through wild-type IDH2. IDH2-dependent changes in intracellular α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG) contribute to EBV-LMP1-induced tumorigenesisin vitroandin vivo. Elevated serum 2-HG level is associated with high EBV DNA and viral capsid antigen-immunoglobulin A (VCA-IgA) levels in patients with NPC. A significantly positive correlation exists between serum 2-HG level and regional lymph node metastases of NPC. EBV-LMP1 enhances the binding of c-Myc with theIDH2promoter and transcriptionally activates wild-type IDH2 through c-Myc. Targeting IDH2 decreased intracellular 2-HG levels and survival of EBV-LMP1-positive tumor cellsin vitroandin vivo.ConclusionsOur results demonstrate that the EBV-LMP1/c-Myc/IDH2WTsignaling axis is critical for EBV-dependent metabolic changes and tumorigenesis, which may provide new insights into EBV-related cancer diagnosis and therapy.