Epstein-Barr virus-driven metabolic alterations contribute to the viral lytic reactivation and tumor progression in nasopharyngeal carcinoma

  • J Med Virol. 2024 May;96(5):e29634. doi: 10.1002/jmv.29634.
Feng Shi  1  2  3 ,  Li Shang  1  2  3 ,  Min Zhou  1  2  3 ,  Cong Lv  4 ,  Yueshuo Li  1  3 ,  Cheng Luo  1  2  3 ,  Na Liu  1  3 ,  Jingchen Lu  1  3 ,  Min Tang  1  3  5  6 ,  Xiangjian Luo  1  3  5  6 ,  Jing Xu  7 ,  Jia Fan  8 ,  Jian Zhou  8 ,  Qiang Gao  8 ,  Weizhong Wu  8 ,  Weihua Jia  9 ,  Hailin Wang  4 ,  Ya Cao  1  3  5  6  10  11
Affiliations
  • 1. Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha, China.
  • 2. Department of Pathology, National Clinical Research Center for Geriatric Disorders/XiangYa Hospital, Central South University, Changsha, China.
  • 3. Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China.
  • 4. State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
  • 5. Department of Radiology, National Clinical Research Center for Geriatric Disorders/XiangYa Hospital, Central South University, Changsha, China.
  • 6. Molecular Imaging Research Center of Central South University, Changsha, China.
  • 7. Department of Otolaryngology Head and Neck Surgery, National Clinical Research Center for Geriatric Disorders/XiangYa Hospital, Central South University, Changsha, China.
  • 8. Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
  • 9. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 10. Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, Changsha, China.
  • 11. National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha, China.
PMID: 38682578 DOI: 10.1002/jmv.29634
Abstract

Metabolic reprogramming induced by Epstein-Barr virus (EBV) often mirrors metabolic changes observed in Cancer cells. Accumulating evidence suggests that lytic reactivation is crucial in EBV-associated oncogenesis. The aim of this study was to explore the role of metabolite changes in EBV-associated malignancies and viral life cycle control. We first revealed that EBV (LMP1) accelerates the secretion of the oncometabolite D-2HG, and serum D-2HG level is a potential diagnostic biomarker for NPC. EBV (LMP1)-driven metabolite changes disrupts the homeostasis of global DNA methylation and demethylation, which have a significantly inhibitory effect on active DNA demethylation and 5hmC content. We found that loss of 5hmC indicates a poor prognosis for NPC patients, and that 5hmC modification is a restriction factor of EBV reactivation. We confirmed a novel EBV reactivation inhibitor, α-KG, which inhibits the expression of EBV lytic genes with CpG-containing ZREs and the latent-lytic switch by enhancing 5hmC modification. Our results demonstrate a novel mechanism of which metabolite abnormality driven by EBV controls the viral lytic reactivation through epigenetic modification. This study presents a potential strategy for blocking EBV reactivation, and provides potential targets for the diagnosis and therapy of NPC.

Keywords
5‐hydroxymethylcytosine; DNA demethylation; D‐2‐hydroxyglutarate; Epstein‐Barr virus; viral lytic reactivation; α‐ketoglutarate.
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