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; Shuang Jian 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

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, Shuang Jian Qiu, Weizhong Wu, Xin Zhang, Weihua Jia, Ann M. Bode, Ya Cao

Hormel Institute

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	100966
Journal	Molecular Metabolism
Volume	36
DOIs	https://doi.org/10.1016/j.molmet.2020.02.009
State	Published - Jun 2020

Bibliographical note

Funding Information:
This study was supported by National Natural Science Foundation of China ( 81430064 , 81602402 , 81874172 ) and Hunan Provincial Natural Science Foundation of China ( 2018JJ3700 ).

Publisher Copyright:
© 2020

Keywords

Epstein-Barr virus
Isocitrate dehydrogenase 2
Metabolic reprogramming
Nasopharyngeal carcinoma
Tumorigenesis

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Shi, F., He, Y., Li, J., Tang, M., Li, Y., Xie, L., Zhao, L., Hu, J., Luo, X., Zhou, M., Liu, N., Fan, J., Zhou, J., Gao, Q., Qiu, S. J., Wu, W., Zhang, X., Jia, W., Bode, A. M., & Cao, Y. (2020). Wild-type IDH2 contributes to Epstein–Barr virus-dependent metabolic alterations and tumorigenesis. Molecular Metabolism, 36, Article 100966. https://doi.org/10.1016/j.molmet.2020.02.009

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title = "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.",

keywords = "Epstein-Barr virus, Isocitrate dehydrogenase 2, Metabolic reprogramming, Nasopharyngeal carcinoma, Tumorigenesis",

author = "Feng Shi and Ya He and Jiangjiang Li and Min Tang and Yueshuo Li and Longlong Xie and Lin Zhao and Jianmin Hu and Xiangjian Luo and Min Zhou and Na Liu and Jia Fan and Jian Zhou and Qiang Gao and Qiu, {Shuang Jian} and Weizhong Wu and Xin Zhang and Weihua Jia and Bode, {Ann M.} and Ya Cao",

note = "Funding Information: This study was supported by National Natural Science Foundation of China ( 81430064 , 81602402 , 81874172 ) and Hunan Provincial Natural Science Foundation of China ( 2018JJ3700 ). Publisher Copyright: {\textcopyright} 2020",

year = "2020",

month = jun,

doi = "10.1016/j.molmet.2020.02.009",

language = "English (US)",

volume = "36",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier GmbH",

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TY - JOUR

T1 - Wild-type IDH2 contributes to Epstein–Barr virus-dependent metabolic alterations and tumorigenesis

AU - Shi, Feng

AU - He, Ya

AU - Li, Jiangjiang

AU - Tang, Min

AU - Li, Yueshuo

AU - Xie, Longlong

AU - Zhao, Lin

AU - Hu, Jianmin

AU - Luo, Xiangjian

AU - Zhou, Min

AU - Liu, Na

AU - Fan, Jia

AU - Zhou, Jian

AU - Gao, Qiang

AU - Qiu, Shuang Jian

AU - Wu, Weizhong

AU - Zhang, Xin

AU - Jia, Weihua

AU - Bode, Ann M.

AU - Cao, Ya

N1 - Funding Information: This study was supported by National Natural Science Foundation of China ( 81430064 , 81602402 , 81874172 ) and Hunan Provincial Natural Science Foundation of China ( 2018JJ3700 ). Publisher Copyright: © 2020

PY - 2020/6

Y1 - 2020/6

N2 - 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.

AB - 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.

KW - Epstein-Barr virus

KW - Isocitrate dehydrogenase 2

KW - Metabolic reprogramming

KW - Nasopharyngeal carcinoma

KW - Tumorigenesis

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SN - 2212-8778

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access

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