Wild-type IDH2 contributes to Epstein-Barr virus-dependent metabolic alterations and tumorigenesis.

Abstract

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.

• Authors: Feng Shi, Ya He, Jiangjiang Li, Min Tang, Yueshuo Li, Longlong Xie, Lin Zhao, Jianmin Hu, Xiangjian Luo, Min Zhou, Na Liu, Jia Fan, Jian Zhou, Qiang Gao, ShuangJian Qiu, Weizhong Wu, Xin Zhang, Weihua Jia, Ann M Bode, Ya Cao
• Journal: Molecular metabolism (Mol Metab) Vol. 36 Pg. 100966 (06 2020) ISSN: 2212-8778 [Electronic] Germany
• PMID: 32224436 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020. Published by Elsevier GmbH.

Chemical References

• EBV-associated membrane antigen, Epstein-Barr virus
• Viral Matrix Proteins
• IDH2 protein, human
• Isocitrate Dehydrogenase

Topics

• Animals
• Carcinogenesis (genetics, metabolism)
• Cell Line
• Cell Line, Tumor
• China
• Databases, Genetic
• Epstein-Barr Virus Infections (metabolism)
• Female
• Herpesvirus 4, Human (pathogenicity)
• Humans
• Isocitrate Dehydrogenase (metabolism, physiology)
• Male
• Mice
• Mice, Nude
• Nasopharyngeal Carcinoma (genetics, metabolism, virology)
• Nasopharyngeal Neoplasms (genetics, metabolism, virology)
• Promoter Regions, Genetic (genetics)
• Signal Transduction
• Viral Matrix Proteins (metabolism)
• Xenograft Model Antitumor Assays