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Updated: Dec 25, 2025
Metabolic Mapping: Quantitative Enzyme Cytochemistry and Histochemistry to Determine the Activity of Dehydrogenases in Cells and Tissues
Published on: May 26, 2018
Wild-type IDH2 contributes to Epstein-Barr virus-dependent metabolic alterations and tumorigenesis
Feng Shi1, Ya He1, Jiangjiang Li1
1Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha 410078, China; Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, China.
Objective:
Epstein-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).
Methods:
Mechanistic 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 staining in vitro and xenograft assays in vivo.
Results:
IDH2 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 tumorigenesis in vitro and in 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 the IDH2 promoter and transcriptionally activates wild-type IDH2 through c-Myc. Targeting IDH2 decreased intracellular 2-HG levels and survival of EBV-LMP1-positive tumor cells in vitro and in vivo.
Conclusions:
Our results demonstrate that the EBV-LMP1/c-Myc/IDH2WT signaling axis is critical for EBV-dependent metabolic changes and tumorigenesis, which may provide new insights into EBV-related cancer diagnosis and therapy.
Insights
Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) upregulates wild-type isocitrate dehydrogenase 2 (IDH2) via c-Myc, driving metabolic reprogramming and tumorigenesis in nasopharyngeal carcinoma. Targeting IDH2 inhibits tumor growth and viability.
Area of Science:
- Oncology
- Virology
- Metabolic Engineering
Background:
- Epstein-Barr virus (EBV) is an oncogenic virus known to reprogram host cell metabolism.
- Latent membrane protein 1 (LMP1), encoded by EBV, is implicated in viral tumorigenesis.
- Isocitrate dehydrogenase 2 (IDH2) plays a role in cellular metabolism and has been linked to cancer progression.
Purpose of the Study:
- To investigate the role of wild-type isocitrate dehydrogenase 2 (IDH2) in metabolic reprogramming and tumorigenesis induced by EBV-encoded latent membrane protein 1 (LMP1).
Main Methods:
- Utilized western blotting, PCR, immunochemistry, ChIP, and luciferase assays to dissect IDH2 function.
- Assessed cell viability and tumor growth in vitro and in vivo using cell assays and xenograft models.
- Measured intracellular metabolites α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), and serum 2-HG levels.
Main Results:
- IDH2 overexpression correlates with poorer survival in head and neck squamous cell carcinoma (HNSCC) and is upregulated in EBV-LMP1-positive nasopharyngeal carcinoma (NPC).
- EBV-LMP1 promotes NPC cell viability and tumor growth through wild-type IDH2, altering α-KG and 2-HG levels.
- EBV-LMP1 enhances c-Myc binding to the IDH2 promoter, transcriptionally activating wild-type IDH2. Elevated serum 2-HG correlates with NPC progression and metastasis.
Conclusions:
- The EBV-LMP1/c-Myc/IDH2 signaling axis is crucial for EBV-driven metabolic alterations and tumorigenesis.
- Targeting IDH2 reduces intracellular 2-HG and inhibits the survival of EBV-LMP1-positive tumor cells.
- This pathway offers potential therapeutic targets for EBV-related cancers.
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