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Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses
- Source :
- PLoS Pathogens, Vol 16, Iss 8, p e1008778 (2020), PLoS Pathogens
- Publication Year :
- 2020
- Publisher :
- Public Library of Science (PLoS), 2020.
-
Abstract
- EBV-associated gastric cancer (EBVaGC) is characterized by high frequency of DNA methylation. In this study, we investigated how epigenetic alteration of host genome contributes to pathogenesis of EBVaGC through the analysis of transcriptomic and epigenomic datasets from NIH TCGA (The Cancer Genome Atlas) consortium. We identified that immune related genes (IRGs) is a group of host genes preferentially silenced in EBV-positive gastric cancers through DNA hypermethylation. Further functional characterizations of selected IRGs reveal their novel antiviral activity against not only EBV but also KSHV. In particular, we showed that metallothionein-1 (MT1) and homeobox A (HOXA) gene clusters are down-regulated via EBV-driven DNA hypermethylation. Several MT1 isoforms suppress EBV lytic replication and release of progeny virions as well as KSHV lytic reactivation, suggesting functional redundancy of these genes. In addition, single HOXA10 isoform exerts antiviral activity against both EBV and KSHV. We also confirmed the antiviral effect of other dysregulated IRGs, such as IRAK2 and MAL, in scenario of EBV and KSHV lytic reactivation. Collectively, our results demonstrated that epigenetic silencing of IRGs is a viral strategy to escape immune surveillance and promote viral propagation, which is overall beneficial to viral oncogenesis of human gamma-herpesviruses (EBV and KSHV), considering that these IRGs possess antiviral activities against these oncoviruses.<br />Author summary Epstein-Barr virus (EBV), one of the human gamma-herpesviruses, is a well-defined viral agent that strongly associates with malignancies of lymphoid and epithelial origin. EBV-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. In this paper, we identified that beyond tumor suppressor genes, immune related genes (IRGs) are another group of host genes that are extensively DNA hypermethylated and epigenetically silenced in EBVaGC comparing to non-EBV GC. For certain IRGs, such as metallothionein-1 (MT1) and homeobox A (HOXA) genes, the whole gene clusters undergo DNA hypermethylation in EBVaGC, while it also occurs for isolated individual IRGs, such as IRAK2 and MAL. Considering the critical role of innate immunity in antiviral control, we expected that silencing of IRGs would benefit EBV viral replication and propagation. Indeed, our further investigation of several IRGs (MT1G, HOXA10, IRAK2, and MAL) confirmed their antiviral activities against EBV lytic replication. Some of them also suppress lytic replication of another human gamma-herpesvirus, Kaposi’s sarcoma-associated herpesvirus (KSHV), indicating their broad antiviral spectrum. Collectively, our results demonstrated that epigenetic silencing of antiviral IRGs is an efficient viral strategy utilized by oncoviruses, such as EBV, to escape immune surveillance and promote viral propagation, which is overall beneficial to viral oncogenesis.
- Subjects :
- viruses
medicine.disease_cause
Pathology and Laboratory Medicine
Virus Replication
Biochemistry
Suppressor Genes
Epigenesis, Genetic
Medicine and Health Sciences
Biology (General)
IRGs
Epigenomics
0303 health sciences
DNA methylation
Incidence
030302 biochemistry & molecular biology
Microbial Genetics
Kaposi's Sarcoma-Associated Herpesvirus
Herpesviridae Infections
Chromatin
Nucleic acids
Lytic cycle
Oncology
Medical Microbiology
Viral Pathogens
Viruses
Host-Pathogen Interactions
Viral Genetics
Epigenetics
Pathogens
DNA modification
Chromatin modification
Research Article
Chromosome biology
Gene Expression Regulation, Viral
Cell biology
Herpesviruses
QH301-705.5
Tumor Suppressor Genes
Immunology
Biology
Microbiology
03 medical and health sciences
Gammaherpesvirinae
Gene Types
Stomach Neoplasms
Virology
Gastrointestinal Tumors
medicine
Genetics
Humans
Kaposi's sarcoma-associated herpesvirus
Molecular Biology
Gene
Microbial Pathogens
030304 developmental biology
Biology and life sciences
Organisms
Cancers and Neoplasms
DNA
RC581-607
Viral Replication
Gastric Cancer
Viral Gene Expression
HEK293 Cells
Homeobox A10 Proteins
Viral replication
Cancer research
Parasitology
Metallothionein
Virus Activation
Gene expression
Immunologic diseases. Allergy
DNA viruses
Biomarkers
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 16
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....2824d3e4f5dda1898b1208390e63e6c3