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

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

doi:10.1016/j.molmet.2020.02.009

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

Mol Metab. 2020 Jun:36:100966. doi: 10.1016/j.molmet.2020.02.009. Epub 2020 Feb 18.

Authors

Feng Shi¹, Ya He¹, Jiangjiang Li¹, Min Tang², Yueshuo Li¹, Longlong Xie¹, Lin Zhao¹, Jianmin Hu¹, Xiangjian Luo², Min Zhou¹, Na Liu¹, Jia Fan³, Jian Zhou³, Qiang Gao³, ShuangJian Qiu³, Weizhong Wu³, Xin Zhang⁴, Weihua Jia⁵, Ann M Bode⁶, Ya Cao⁷

Affiliations

¹ Key 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.
² Key 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; Molecular Imaging Research Center of Central South University, Changsha 410008, Hunan, China.
³ Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200000, China.
⁴ Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410078, China.
⁵ State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
⁶ The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
⁷ Key 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; Molecular Imaging Research Center of Central South University, Changsha 410008, Hunan, China; Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, Changsha 410078, China; National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha 410078, China. Electronic address: ycao98@vip.sina.com.

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/IDH2^WT signaling axis is critical for EBV-dependent metabolic changes and tumorigenesis, which may provide new insights into EBV-related cancer diagnosis and therapy.

Keywords: Epstein-Barr virus; Isocitrate dehydrogenase 2; Metabolic reprogramming; Nasopharyngeal carcinoma; Tumorigenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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