scholarly journals Epstein-Barr Virus Facilitates Expression of KLF14 by Regulating the Cooperative Binding of the E2F-Rb-HDAC Complex in Latent Infection

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Yonggang Pei ◽  
Josiah Hiu-yuen Wong ◽  
Hem Chandra Jha ◽  
Tian Tian ◽  
Zhi Wei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Population ◽  
Regulatory Networks ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Human Tumor ◽  
Barr Virus ◽  
Repressor Complex ◽  
Tumor Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) was discovered as the first human tumor virus more than 50 years ago. EBV infects more than 90% of the human population worldwide and is associated with numerous hematologic malignancies and epithelial malignancies. EBV establishes latent infection in B cells, which is the typical program seen in lymphomagenesis. Understanding EBV-mediated transcription regulatory networks is one of the current challenges that will uncover new insights into the mechanism of viral-mediated lymphomagenesis. Here, we describe the regulatory profiles of several cellular factors (E2F6, E2F1, Rb, HDAC1, and HDAC2) together with EBV latent nuclear antigens using next-generation sequencing (NGS) analysis. Our results show that the E2F-Rb-HDAC complex exhibits similar distributions in genomic regions of EBV-positive cells and is associated with oncogenic super-enhancers involving long-range regulatory regions. Furthermore, EBV latent antigens cooperatively hijack this complex to bind at KLFs gene loci and facilitate KLF14 gene expression in lymphoblastoid cell lines (LCLs). These results demonstrate that EBV latent antigens can function as master regulators of this multisubunit repressor complex (E2F-Rb-HDAC) to reverse its suppressive activities and facilitate downstream gene expression that can contribute to viral-induced lymphomagenesis. These results provide novel insights into targets for the development of new therapeutic interventions for treating EBV-associated lymphomas. IMPORTANCE Epstein-Barr virus (EBV), as the first human tumor virus, infects more than 90% of the human population worldwide and is associated with numerous human cancers. Exploring EBV-mediated transcription regulatory networks is critical to understand viral-associated lymphomagenesis. However, the detailed mechanism is not fully explored. Now we describe the regulatory profiles of the E2F-Rb-HDAC complex together with EBV latent antigens, and we found that EBV latent antigens cooperatively facilitate KLF14 expression by antagonizing this multisubunit repressor complex in EBV-positive cells. This provides potential therapeutic targets for the treatment of EBV-associated cancers.

EBV+ Lymphoproliferative Diseases: Opportunities for leveraging EBV as a Therapeutic Target

Blood ◽  
2021 ◽  
Author(s):  
Keri Toner ◽  
Catherine M. Bollard
Keyword(s):  
Proliferative Response ◽  
Epstein Barr Virus ◽  
Human Tumor ◽  
Lymphoproliferative Disease ◽  
Lymphoproliferative Diseases ◽  
Malignant Lymphomas ◽  
Barr Virus ◽  
Immune Therapies ◽  
Tumor Virus ◽  
Epstein Barr

Epstein-Barr virus (EBV) is a ubiquitous human tumor virus, which contributes to the development of lymphoproliferative disease, most notably in patients with impaired immunity. EBV associated lymphoproliferation is characterized by expression of latent EBV proteins and ranges in severity from a relatively benign proliferative response to aggressive malignant lymphomas. The presence of EBV can also serve as a unique target for directed therapies for the treatment of EBV lymphoproliferative diseases, including T cell based immune therapies. In this review, we will describe the EBV-associated lymphoproliferative diseases and will particularly focus on the therapies that target EBV.

scholarly journals Epstein-Barr Virus Infection Promotes Epithelial Cell Growth by Attenuating Differentiation-Dependent Exit from the Cell Cycle

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Mark R. Eichelberg ◽  
Rene Welch ◽  
J. Tod Guidry ◽  
Ahmed Ali ◽  
Makoto Ohashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Oral Epithelial

ABSTRACT Epstein-Barr virus (EBV) is a human herpesvirus that is associated with lymphomas as well as nasopharyngeal and gastric carcinomas. Although carcinomas account for almost 90% of EBV-associated cancers, progress in examining EBV’s role in their pathogenesis has been limited by difficulty in establishing latent infection in nontransformed epithelial cells. Recently, EBV infection of human telomerase reverse transcriptase (hTERT)-immortalized normal oral keratinocytes (NOKs) has emerged as a model that recapitulates aspects of EBV infection in vivo, such as differentiation-associated viral replication. Using uninfected NOKs and NOKs infected with the Akata strain of EBV (NOKs-Akata), we examined changes in gene expression due to EBV infection and differentiation. Latent EBV infection produced very few significant gene expression changes in undifferentiated NOKs but significantly reduced the extent of differentiation-induced gene expression changes. Gene set enrichment analysis revealed that differentiation-induced downregulation of the cell cycle and metabolism pathways was markedly attenuated in NOKs-Akata relative to that in uninfected NOKs. We also observed that pathways induced by differentiation were less upregulated in NOKs-Akata. We observed decreased differentiation markers and increased suprabasal MCM7 expression in NOKs-Akata versus NOKs when both were grown in raft cultures, consistent with our transcriptome sequencing (RNA-seq) results. These effects were also observed in NOKs infected with a replication-defective EBV mutant (AkataΔRZ), implicating mechanisms other than lytic-gene-induced host shutoff. Our results help to define the mechanisms by which EBV infection alters keratinocyte differentiation and provide a basis for understanding the role of EBV in epithelial cancers. IMPORTANCE Latent infection by Epstein-Barr virus (EBV) is an early event in the development of EBV-associated carcinomas. In oral epithelial tissues, EBV establishes a lytic infection of differentiated epithelial cells to facilitate the spread of the virus to new hosts. Because of limitations in existing model systems, the effects of latent EBV infection on undifferentiated and differentiating epithelial cells are poorly understood. Here, we characterize latent infection of an hTERT-immortalized oral epithelial cell line (NOKs). We find that although EBV expresses a latency pattern similar to that seen in EBV-associated carcinomas, infection of undifferentiated NOKs results in differential expression of a small number of host genes. In differentiating NOKs, however, EBV has a more substantial effect, reducing the extent of differentiation and delaying the exit from the cell cycle. This effect may synergize with preexisting cellular abnormalities to prevent exit from the cell cycle, representing a critical step in the development of cancer.

scholarly journals Modulation of the Cell Growth Regulator mTOR by Epstein-Barr Virus-Encoded LMP2A

2005 ◽  
Vol 79 (9) ◽  
pp. 5499-5506 ◽  
Author(s):  
Cary A. Moody ◽  
Rona S. Scott ◽  
Nazanin Amirghahari ◽  
Cherie-Ann Nathan ◽  
Lawrence S. Young ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Mammalian Target Of Rapamycin ◽  
Human Tumor ◽  
Protein Translation ◽  
Negative Regulator ◽  
Initiation Factor ◽  
Barr Virus ◽  
Eukaryotic Initiation Factor 4E ◽  
Tumor Virus ◽  
Epstein Barr

ABSTRACT Control of translation initiation is one means by which cells regulate growth and proliferation, with components of the protein-synthesizing machinery having oncogenic potential. Expression of latency protein LMP2A by the human tumor virus Epstein-Barr virus (EBV) activates phosphatidylinositol 3-kinase/Akt located upstream of an essential mediator of growth signals, mTOR (mammalian target of rapamycin). We show that mTOR is activated by expression of LMP2A in carcinoma cells, leading to wortmannin- and rapamycin-sensitive inhibition of the negative regulator of translation, eukaryotic initiation factor 4E-binding protein 1, and increased c-Myc protein translation. Intervention by this DNA tumor virus in cellular translational controls is likely to be an integral component of EBV tumorigenesis.

scholarly journals Study On the Mechanism of LMP2A Maintaining Epstein-barr Virus Latency Infection Through Interaction With CXCR4

2021 ◽  
Author(s):  
Ni Qin ◽  
Yan Zhang ◽  
Lin Xu ◽  
Wen Liu ◽  
Bing Luo
Keyword(s):  
Gastric Cancer ◽  
Epstein Barr Virus ◽  
Human Tumor ◽  
Signal Pathways ◽  
Barr Virus ◽  
Virus Latency ◽  
Early Protein ◽  
Tumor Virus ◽  
Epstein Barr ◽  
And Migration

Abstract Epstein-Barr virus (EBV) belongs to the γ-herpesvirus subfamily and is the first human tumor virus to be discovered. The global adult infection rate exceeds 90%. EBV can participate in the regulation of multiple genes and multiple signal pathways through its latent genes. Many studies have reported that CXCR4 is involved in the development of gastric cancer, but there are few studies on the specific mechanism of its role in EBV-associated gastric cancer (EBVaGC). In this study, we explored the mechanism by which EBV-encoded products maintain EBV latent infection through interaction with CXCR4, and the role of CXCR4 in EBV positive cells. The results show that there is a positive feedback between the EBV-encoded products and CXCR4, and LMP2A can activate CXCR4 through the NF-κB pathway. In addition, CXCR4 can be fed back to LMP2A and EBNA1 through the ERK signaling pathway. At the same time, CXCR4 can promote the proliferation and migration of EBV-positive cells, reduce the expression of the immediate early protein BZLF1, and play an important role in maintaining the incubation period of EBV infection. These findings are conducive to the further targeted therapy of EBVaGC.

scholarly journals Immune Escape by Non-coding RNAs of the Epstein Barr Virus

2021 ◽  
Vol 12 ◽  
Author(s):  
Christian Münz
Keyword(s):  
Epstein Barr Virus ◽  
Vaccine Development ◽  
Immune Escape ◽  
Human Tumor ◽  
Experimental Models ◽  
Cytotoxic Lymphocytes ◽  
Barr Virus ◽  
Tumor Virus ◽  
Non Coding Rnas ◽  
Epstein Barr

Epstein Barr virus (EBV) is one of the most successful pathogens of humans, persistently colonizing more than 95% of the adult human population. At the same time EBV encodes oncogenes that can readily transform human B cells in culture and threaten healthy virus carriers with lymphomagenesis. Cytotoxic lymphocytes have been identified in experimental models and by primary immunodeficiencies as the main protective immune compartments controlling EBV. EBV has reached a stalemate with these cytotoxic T and innate lymphocytes to ensure persistence in most infected humans. Recent evidence suggests that the non-coding RNAs of the virus contribute to viral immune escape to prevent immune eradication. This knowledge might be used in the future to attenuate EBV for vaccine development against this human tumor virus that was discovered more than 55 years ago.

scholarly journals Epstein-Barr virus reprograms human B-lymphocytes immediately in the pre-latent phase of infection

2018 ◽  
Author(s):  
Paulina Mrozek-Gorska ◽  
Alexander Buschle ◽  
Dagmar Pich ◽  
Thomas Schwarzmayr ◽  
Ron Fechtner ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Metabolic Pathways ◽  
Epstein Barr Virus ◽  
Human Tumor ◽  
Time Resolved ◽  
Barr Virus ◽  
Tumor Virus ◽  
Epstein Barr

AbstractEpstein-Barr virus (EBV) is a human tumor virus and a model of herpesviral latency. The virus efficiently infects resting human B-lymphocytes and induces their continuous proliferation in vitro, which mimics certain aspects of EBV’s oncogenic potential in vivo. This seminal finding was made 50 years ago, but how EBV activates primary human B-lymphocytes and how lymphoblastoid cell lines (LCLs) evolve from the EBV-infected lymphocytes is uncertain. We conducted a systematic time-resolved longitudinal study of cellular functions and transcriptional profiles of newly infected naïve primary B-lymphocytes. EBV reprograms these human cells comprehensively and globally. Rapid and extensive transcriptional changes occur within 24 hours of infection and precede any metabolic and phenotypic changes. Within the next 48 hours, the virus activates the cells, changes their phenotypes with respect to cell size, RNA and protein content and induces metabolic pathways to cope with the increased demand for energy, supporting an efficient cell cycle entry on day three post infection. The transcriptional program that EBV initiates consists of three waves of clearly discernable clusters of cellular genes that peak on day one, two, or three and regulate RNA synthesis, metabolic pathways and cell division, respectively. Upon the onset of cell doublings on day four the cellular transcriptome appears to be completely reprogrammed to support the activated and proliferating cell, but three additional clusters of EBV regulated genes adjust the infected immune cells to fine-tune cell signaling, migration, and immune response pathways, eventually. Our study reveals that more than 98 % of the 13,000 expressed genes in B-lymphocytes are regulated upon infection demonstrating that EBV governs the entire biology of its target cell.

Detection of Epstein-Barr virus genome and latent infection gene expression in normal epithelia, epithelial dysplasia, and squamous cell carcinoma of the oral cavity

Tumor Biology ◽  
2015 ◽  
Vol 37 (3) ◽  
pp. 3389-3404 ◽  
Author(s):  
Kentaro Kikuchi ◽  
Yoshihiro Noguchi ◽  
Michelle Wendoline Garcia-Niño de Rivera ◽  
Miyako Hoshino ◽  
Hideaki Sakashita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Squamous Cell Carcinoma ◽  
Oral Cavity ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Virus Genome ◽  
Barr Virus ◽  
Epstein Barr

Radio-Susceptibility of Nasopharyngeal Carcinoma: Focus on Epstein- Barr Virus, MicroRNAs, Long Non-Coding RNAs and Circular RNAs

2020 ◽  
Vol 13 (3) ◽  
pp. 192-205 ◽  
Author(s):  
Fanghong Lei ◽  
Tongda Lei ◽  
Yun Huang ◽  
Mingxiu Yang ◽  
Mingchu Liao ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Regulatory Networks ◽  
Epstein Barr Virus ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Circular Rnas ◽  
Barr Virus ◽  
Non Coding Rnas ◽  
Epstein Barr

Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer. As a neoplastic disorder, NPC is a highly malignant squamous cell carcinoma that is derived from the nasopharyngeal epithelium. NPC is radiosensitive; radiotherapy or radiotherapy combining with chemotherapy are the main treatment strategies. However, both modalities are usually accompanied by complications and acquired resistance to radiotherapy is a significant impediment to effective NPC therapy. Therefore, there is an urgent need to discover effective radio-sensitization and radio-resistance biomarkers for NPC. Recent studies have shown that Epstein-Barr virus (EBV)-encoded products, microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), which share several common signaling pathways, can function in radio-related NPC cells or tissues. Understanding these interconnected regulatory networks will reveal the details of NPC radiation sensitivity and resistance. In this review, we discuss and summarize the specific molecular mechanisms of NPC radio-sensitization and radio-resistance, focusing on EBV-encoded products, miRNAs, lncRNAs and circRNAs. This will provide a foundation for the discovery of more accurate, effective and specific markers related to NPC radiotherapy. EBVencoded products, miRNAs, lncRNAs and circRNAs have emerged as crucial molecules mediating the radio-susceptibility of NPC. This understanding will improve the clinical application of markers and inform the development of novel therapeutics for NPC.

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