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EBV Infection and Its Regulated Metabolic Reprogramming in Nasopharyngeal Tumorigenesis.

ABSTRACT: Viral oncogenes may drive cellular metabolic reprogramming to modulate the normal epithelia cell malignant transformation. Understanding the viral oncogene-mediated signaling transduction dysregulation that involves in metabolic reprogramming may provide new therapeutic targets for virus-associated cancer treatment. Latent EBV infection and expression of viral oncogenes, including latent membrane proteins 1 and 2 (LMP1/2), and EBV-encoded BamH I-A rightward transcripts (BART) microRNAs (miR-BARTs), have been demonstrated to play fundamental roles in altering host cell metabolism to support nasopharyngeal carcinoma (NPC) pathogenesis. Yet, how do EBV infection and its encoded oncogenes facilitated the metabolic shifting and their roles in NPC carcinogenesis remains unclear. In this review, we will focus on delineating how EBV infection and its encoded oncoproteins altered the metabolic reprograming of infected cells to support their malignances. Furthermore, based on the understanding of the host's metabolic signaling alterations induced by EBV, we will provide a new perspective on the interplay between EBV infection and these metabolic pathways and offering a potential therapeutic intervention strategy in the treatment of EBV-associated malignant diseases.

SUBMITTER: Yang T

PROVIDER: S-EPMC9283984 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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EBV Infection and Its Regulated Metabolic Reprogramming in Nasopharyngeal Tumorigenesis.

Yang Tingting T You Chanping C Meng Shuhui S Lai Zhengquan Z Ai Weipeng W Zhang Jun J

Frontiers in cellular and infection microbiology 20220701

Viral oncogenes may drive cellular metabolic reprogramming to modulate the normal epithelia cell malignant transformation. Understanding the viral oncogene-mediated signaling transduction dysregulation that involves in metabolic reprogramming may provide new therapeutic targets for virus-associated cancer treatment. Latent EBV infection and expression of viral oncogenes, including latent membrane proteins 1 and 2 (LMP1/2), and EBV-encoded BamH I-A rightward transcripts (BART) microRNAs (miR-BART ...[more]

PMID: 35846746

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Project description:BackgroundEpstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in nasopharyngeal carcinoma (NPC).MethodsTo investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data.FindingsIn addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r2 = 0.55).InterpretationOur study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion.FundingThis study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL, General Research Fund (17103218 and 17102619) and seed funding for basic research (201611159158) to WD, and General Research Fund (17119618) to HC.

Project description:Nasopharyngeal carcinoma (NPC) is common among southern Chinese including the ethnic Cantonese population living in Hong Kong. Epstein-Barr virus (EBV) infection is detected in all undifferentiated type of NPC in this endemic region. Establishment of stable and latent EBV infection in premalignant nasopharyngeal epithelial cells is an early event in NPC development and may contribute to its pathogenesis. Immortalized primary nasopharyngeal epithelial cells represent an important tool for investigation of EBV infection and its tumorigenic potential in this special type of epithelial cells. However, the limited availability and small sizes of nasopharyngeal biopsies have seriously restricted the establishment of primary nasopharyngeal epithelial cells for immortalization. A reliable and effective method to immortalize primary nasopharyngeal epithelial cells will provide unrestricted materials for EBV infection studies. An earlier study has reported that Bmi-1 expression could immortalize primary nasopharyngeal epithelial cells. However, its efficiency and actions in immortalization have not been fully characterized. Our studies showed that Bmi-1 expression alone has limited ability to immortalize primary nasopharyngeal epithelial cells and additional events are often required for its immortalization action. We have identified some of the key events associated with the immortalization of primary nasopharyngeal epithelial cells. Efficient immortalization of nasopharyngeal epithelial cells could be reproducibly and efficiently achieved by the combined actions of Bmi-1 expression, activation of telomerase and silencing of p16 gene. Activation of MAPK signaling and gene expression downstream of Bmi-1 were detected in the immortalized nasopharyngeal epithelial cells and may play a role in immortalization. Furthermore, these newly immortalized nasopharyngeal epithelial cells are susceptible to EBV infection and supported a type II latent EBV infection program characteristic of EBV-infected nasopharyngeal carcinoma. The establishment of an efficient method to immortalize primary nasopharyngeal epithelial cells will facilitate the investigation into the role of EBV infection in pathogenesis of nasopharyngeal carcinoma.

Dataset Information

EBV Infection and Its Regulated Metabolic Reprogramming in Nasopharyngeal Tumorigenesis.

Publications

EBV Infection and Its Regulated Metabolic Reprogramming in Nasopharyngeal Tumorigenesis.

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