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

Molecular Metabolism (Jun 2020)

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

Affiliations

Feng Shi: 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
Ya He: 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
Jiangjiang Li: 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
Min Tang: 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
Yueshuo Li: 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
Longlong Xie: 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
Lin Zhao: 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
Jianmin Hu: 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
Xiangjian Luo: 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
Min Zhou: 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
Na Liu: 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
Jia Fan: Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200000, China
Jian Zhou: Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200000, China
Qiang Gao: Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200000, China
ShuangJian Qiu: Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200000, China
Weizhong Wu: Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200000, China
Xin Zhang: Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410078, China
Weihua Jia: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Ann M. Bode: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
Ya Cao: 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; Corresponding author. Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha 410078, China.

Journal volume & issue: Vol. 36

Abstract

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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.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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