Epstein–Barr virus: a master epigenetic manipulator

Scott, Rona S.

doi:10.1016/j.coviro.2017.07.017

Cited by 53 publications

(42 citation statements)

References 83 publications

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“…EBV infection leads to the epigenetic changes, involving DNA methylation and histone modifications, and signaling pathway aberrations in host cells 8 , 46 . Our transcriptome analysis revealed that vasculogenesis-related genes were upregulated in EBV-infected epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Vasculogenic mimicry formation in EBV-associated epithelial malignancies

Xiang¹,

Lin²,

et al. 2018

Nat Commun

141

119

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Epstein-Barr virus (EBV)-associated epithelial cancers, including nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancers, termed EBVaGC, represent 80% of all EBV-related malignancies. However, the exact role of EBV in epithelial cancers remains elusive. Here, we report that EBV functions in vasculogenic mimicry (VM). Epithelial cancer cells infected with EBV develop tumor vascular networks that correlate with tumor growth, which is different from endothelial-derived angiogenic vessels and is VEGF-independent. Mechanistically, activation of the PI3K/AKT/mTOR/HIF-1α signaling cascade, which is partly mediated by LMP2A, is responsible for EBV-induced VM formation. Both xenografts and clinical samples of NPC and EBVaGC exhibit VM histologically, which are correlated with AKT and HIF-1α activation. Furthermore, although anti-VEGF monotherapy shows limited effects, potent synergistic antitumor activities are achieved by combination therapy with VEGF and HIF-1α-targeted agents. Our findings suggest that EBV creates plasticity in epithelial cells to express endothelial phenotype and provides a novel EBV-targeted antitumor strategy.

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Section: Discussionmentioning

confidence: 99%

Vasculogenic mimicry formation in EBV-associated epithelial malignancies

Xiang¹,

Lin²,

et al. 2018

Nat Commun

141

119

View full text Add to dashboard Cite

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“…After EBV infection of host cells, these EBV miRNAs form incomplete complementary pairing with the 3'-untranslated region (3'UTR) of the virus's own genes or host gene mRNAs, resulting in inhibition of gene translation or the degradation of targeted mRNAs [37]. In recent years, many studies have shown that EBV miRNAs can inhibit the expression and presentation of viral antigens by inhibiting the expression of viral genes and host cell genes, inhibiting the activation and cytotoxicity of immune cells, and achieving long-term latency, immune escape, and promotion of host cells immortalization and tumor development [38], which is briefly reviewed below.…”

Section: Ebv Mirnasmentioning

confidence: 99%

Epstein barr virus encodes miRNAs to assist host immune escape

Yang

et al. 2020

J. Cancer

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Epstein-barr virus (EBV) is a definite tumorigenic virus, which can form lifelong latency in the host, which is difficult to be recognized and completely eliminated by the immune system. It is closely related to the occurrence and development of nasopharyngeal cancer, gastric cancer and various types of lymphoma. At present, a total of 44 Epstein-barr virus-encoded microRNAs (EBV miRNAs) have been found. In response to the immune system of the body, EBV miRNAs can inhibit the expression and presentation of viral antigens, inhibit immune activation and immunotoxicity, assisting host cells to escape from immunity, and providing conditions for further immortalized tumorigenesis of the host cells.

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“…We also show that downregulation of KDM2B expression in EBV-infected cells is mediated by DNMT1 recruitment to its gene and by its DNA methylation. It has already been reported that EBV can alter DNMT1 activity through its viral proteins LMP1 and LMP2A (29). In particular, Tsai and colleagues showed that LMP1 activates DNMT1 activity (15) and that this event requires activation of the JNK/AP1 pathway.…”

Section: Discussionmentioning

confidence: 99%

Interplay between the Epigenetic Enzyme Lysine (K)-Specific Demethylase 2B and Epstein-Barr Virus Infection

Vargas-Ayala

Jay

Manara

et al. 2019

J Virol

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The histone modifier lysine (K)-specific demethylase 2B (KDM2B) plays a role in the differentiation of hematopoietic cells, and its expression appears to be deregulated in certain cancers of hematological and lymphoid origins. We have previously found that the KDM2B gene is differentially methylated in cell lines derived from Epstein-Barr virus (EBV)-associated endemic Burkitt lymphoma (eBL) compared with that in EBV-negative sporadic Burkitt lymphoma-derived cells. However, whether KDM2B plays a role in eBL development has not been previously investigated. Oncogenic viruses have been shown to hijack the host cell epigenome to complete their life cycle and to promote the transformation process by perturbing cell chromatin organization. Here, we investigated whether EBV alters KDM2B levels to enable its life cycle and promote B-cell transformation. We show that infection of B cells with EBV leads to downregulation of KDM2B levels. We also show that LMP1, one of the main EBV transforming proteins, induces increased DNMT1 recruitment to the KDM2B gene and augments its methylation. By altering KDM2B levels and performing chromatin immunoprecipitation in EBV-infected B cells, we show that KDM2B is recruited to the EBV gene promoters and inhibits their expression. Furthermore, forced KDM2B expression in immortalized B cells led to altered mRNA levels of some differentiation-related genes. Our data show that EBV deregulates KDM2B levels through an epigenetic mechanism and provide evidence for a role of KDM2B in regulating virus and host cell gene expression, warranting further investigations to assess the role of KDM2B in the process of EBV-mediated lymphomagenesis. IMPORTANCE In Africa, Epstein-Barr virus infection is associated with endemicBurkitt lymphoma, a pediatric cancer. The molecular events leading to its development are poorly understood compared with those leading to sporadic Burkitt lymphoma. In a previous study, by analyzing the DNA methylation changes in endemic compared with sporadic Burkitt lymphoma cell lines, we identified several differential methylated genomic positions in the proximity of genes with a potential role in cancer, and among them was the KDM2B gene. KDM2B encodes a histone H3 demethylase already shown to be involved in some hematological disorders. However, whether KDM2B plays a role in the development of Epstein-Barr virus-mediated lymphoma has not been investigated before. In this study, we show that Epstein-Barr virus deregulates KDM2B expression and describe the underlying mechanisms. We Citation Vargas-Ayala RC, also reveal a role of the demethylase in controlling viral and B-cell gene expression, thus highlighting a novel interaction between the virus and the cellular epigenome.

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Epstein–Barr virus: a master epigenetic manipulator

Cited by 53 publications

References 83 publications

Vasculogenic mimicry formation in EBV-associated epithelial malignancies

Vasculogenic mimicry formation in EBV-associated epithelial malignancies

Epstein barr virus encodes miRNAs to assist host immune escape

Interplay between the Epigenetic Enzyme Lysine (K)-Specific Demethylase 2B and Epstein-Barr Virus Infection

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