Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses
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...
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| creator | Fiches, Guillaume N Zhou, Dawei Kong, Weili Biswas, Ayan Ahmed, Elshafa H Baiocchi, Robert A Zhu, Jian Santoso, Netty |
| description | 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. |
| doi_str_mv | 10.1371/journal.ppat.1008778 |
| format | Article |
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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.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1008778</identifier><identifier>PMID: 32841292</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Antiviral activity ; Biology and life sciences ; Biomarkers - analysis ; Biomarkers - metabolism ; Cancer ; Care and treatment ; Complications and side effects ; Consortia ; Deoxyribonucleic acid ; Development and progression ; DNA ; DNA Methylation ; Epigenesis, Genetic ; Epigenetics ; Epstein-Barr virus diseases ; Gammaherpesvirinae - genetics ; Gammaherpesvirinae - isolation & purification ; Gastric cancer ; Gene clusters ; Gene expression ; Gene Expression Regulation, Viral ; Gene mutations ; Gene silencing ; Genes ; Genetic aspects ; Genomes ; Health aspects ; HEK293 Cells ; Hematology ; Herpesviridae Infections - complications ; Herpesviridae Infections - virology ; Homeobox ; Homeobox A10 Proteins - genetics ; Host-Pathogen Interactions ; Humans ; Immune response ; Immunosurveillance ; Incidence ; Infections ; Internal medicine ; IRAK protein ; Isoforms ; Kaposis sarcoma ; Medical schools ; Medicine ; Medicine and Health Sciences ; Metallothionein ; Metallothionein - genetics ; Oncogenes ; Pathogenesis ; Pathology ; Progeny ; Proteins ; Redundancy ; Stomach cancer ; Stomach Neoplasms - epidemiology ; Stomach Neoplasms - genetics ; Stomach Neoplasms - metabolism ; Stomach Neoplasms - virology ; Tumorigenesis ; Tumors ; Viral infections ; Virions ; Virus Activation ; Virus Replication ; Viruses</subject><ispartof>PLoS pathogens, 2020-08, Vol.16 (8), p.e1008778-e1008778</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Fiches et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Fiches et al 2020 Fiches et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c661t-cb29fa80224c295a41e0895aa50ff5d1efd1995c0f6d1667d11869b18d3e60383</citedby><cites>FETCH-LOGICAL-c661t-cb29fa80224c295a41e0895aa50ff5d1efd1995c0f6d1667d11869b18d3e60383</cites><orcidid>0000-0003-1175-5831 ; 0000-0003-3515-8417</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473590/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473590/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32841292$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Feng, Pinghui</contributor><creatorcontrib>Fiches, Guillaume N</creatorcontrib><creatorcontrib>Zhou, Dawei</creatorcontrib><creatorcontrib>Kong, Weili</creatorcontrib><creatorcontrib>Biswas, Ayan</creatorcontrib><creatorcontrib>Ahmed, Elshafa H</creatorcontrib><creatorcontrib>Baiocchi, Robert A</creatorcontrib><creatorcontrib>Zhu, Jian</creatorcontrib><creatorcontrib>Santoso, Netty</creatorcontrib><title>Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>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.</description><subject>Activation</subject><subject>Antiviral activity</subject><subject>Biology and life sciences</subject><subject>Biomarkers - analysis</subject><subject>Biomarkers - metabolism</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Complications and side effects</subject><subject>Consortia</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Epstein-Barr virus diseases</subject><subject>Gammaherpesvirinae - genetics</subject><subject>Gammaherpesvirinae - isolation & purification</subject><subject>Gastric cancer</subject><subject>Gene clusters</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Viral</subject><subject>Gene mutations</subject><subject>Gene silencing</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Health aspects</subject><subject>HEK293 Cells</subject><subject>Hematology</subject><subject>Herpesviridae Infections - complications</subject><subject>Herpesviridae Infections - virology</subject><subject>Homeobox</subject><subject>Homeobox A10 Proteins - genetics</subject><subject>Host-Pathogen Interactions</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immunosurveillance</subject><subject>Incidence</subject><subject>Infections</subject><subject>Internal medicine</subject><subject>IRAK protein</subject><subject>Isoforms</subject><subject>Kaposis sarcoma</subject><subject>Medical schools</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Metallothionein</subject><subject>Metallothionein - genetics</subject><subject>Oncogenes</subject><subject>Pathogenesis</subject><subject>Pathology</subject><subject>Progeny</subject><subject>Proteins</subject><subject>Redundancy</subject><subject>Stomach cancer</subject><subject>Stomach Neoplasms - epidemiology</subject><subject>Stomach Neoplasms - genetics</subject><subject>Stomach Neoplasms - metabolism</subject><subject>Stomach Neoplasms - virology</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Viral infections</subject><subject>Virions</subject><subject>Virus Activation</subject><subject>Virus Replication</subject><subject>Viruses</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqVk81u1DAUhSMEoqXwBggisYHFDHbsOPEGqVQFRqoA8be1PPZ1xlViB9sZwUPwzng6adVB3aBIcX6-c27uiW9RPMVoiUmDX1_6KTjZL8dRpiVGqG2a9l5xjOuaLBrS0Pu3ro-KRzFeIkQxwexhcUSqluKKV8fFn8_BG9tb15XelHYYJgdlgF4m0GUHDmIZbQ9O5VvryvO3PxajjzbZLZSdjClYVSoZlHV-kKXV4JI1NsPOb6HPTldIst6VRqrkQ9zV2UyDdFk_DHIDYYS4tWGKEB8XD4zsIzyZ15Pi-7vzb2cfFhef3q_OTi8WijGcFmpdcSNbVFVUVbyWFANq8yprZEytMRiNOa8VMkxjxhqNccv4GreaAEOkJSfF873v2Pso5iSjqCglDBPKeCZWe0J7eSnGYAcZfgsvrbh64EMnZEhW9SA4J2uKKKMMKOVaS0Q1UflcEdXqNWSvN3O1aT2AVjmjIPsD08M3zm5E57eioQ2pOcoGL2eD4H9OOVIx2Kig76UDP-2-O_9jRGuOM_riH_Tu7maqk7kB64zPddXOVJwyQrMfaVimlndQ-dAwWOUd5I0Dh4JXB4LMJPiVOjnFKFZfv_wH-_GQpXtWBR9jAHOTHUZiNwzXTYrdMIh5GLLs2e3cb0TXu5_8BUnEB68</recordid><startdate>20200801</startdate><enddate>20200801</enddate><creator>Fiches, Guillaume N</creator><creator>Zhou, Dawei</creator><creator>Kong, Weili</creator><creator>Biswas, Ayan</creator><creator>Ahmed, Elshafa H</creator><creator>Baiocchi, Robert A</creator><creator>Zhu, Jian</creator><creator>Santoso, Netty</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-1175-5831</orcidid><orcidid>https://orcid.org/0000-0003-3515-8417</orcidid></search><sort><creationdate>20200801</creationdate><title>Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses</title><author>Fiches, Guillaume N ; Zhou, Dawei ; Kong, Weili ; Biswas, Ayan ; Ahmed, Elshafa H ; Baiocchi, Robert A ; Zhu, Jian ; Santoso, Netty</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c661t-cb29fa80224c295a41e0895aa50ff5d1efd1995c0f6d1667d11869b18d3e60383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Activation</topic><topic>Antiviral activity</topic><topic>Biology and life sciences</topic><topic>Biomarkers - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fiches, Guillaume N</au><au>Zhou, Dawei</au><au>Kong, Weili</au><au>Biswas, Ayan</au><au>Ahmed, Elshafa H</au><au>Baiocchi, Robert A</au><au>Zhu, Jian</au><au>Santoso, Netty</au><au>Feng, Pinghui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2020-08-01</date><risdate>2020</risdate><volume>16</volume><issue>8</issue><spage>e1008778</spage><epage>e1008778</epage><pages>e1008778-e1008778</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32841292</pmid><doi>10.1371/journal.ppat.1008778</doi><orcidid>https://orcid.org/0000-0003-1175-5831</orcidid><orcidid>https://orcid.org/0000-0003-3515-8417</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central Open Access; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Activation Antiviral activity Biology and life sciences Biomarkers - analysis Biomarkers - metabolism Cancer Care and treatment Complications and side effects Consortia Deoxyribonucleic acid Development and progression DNA DNA Methylation Epigenesis, Genetic Epigenetics Epstein-Barr virus diseases Gammaherpesvirinae - genetics Gammaherpesvirinae - isolation & purification Gastric cancer Gene clusters Gene expression Gene Expression Regulation, Viral Gene mutations Gene silencing Genes Genetic aspects Genomes Health aspects HEK293 Cells Hematology Herpesviridae Infections - complications Herpesviridae Infections - virology Homeobox Homeobox A10 Proteins - genetics Host-Pathogen Interactions Humans Immune response Immunosurveillance Incidence Infections Internal medicine IRAK protein Isoforms Kaposis sarcoma Medical schools Medicine Medicine and Health Sciences Metallothionein Metallothionein - genetics Oncogenes Pathogenesis Pathology Progeny Proteins Redundancy Stomach cancer Stomach Neoplasms - epidemiology Stomach Neoplasms - genetics Stomach Neoplasms - metabolism Stomach Neoplasms - virology Tumorigenesis Tumors Viral infections Virions Virus Activation Virus Replication Viruses |
| title | Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T12%3A49%3A54IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Profiling%20of%20immune%20related%20genes%20silenced%20in%20EBV-positive%20gastric%20carcinoma%20identified%20novel%20restriction%20factors%20of%20human%20gammaherpesviruses&rft.jtitle=PLoS%20pathogens&rft.au=Fiches,%20Guillaume%20N&rft.date=2020-08-01&rft.volume=16&rft.issue=8&rft.spage=e1008778&rft.epage=e1008778&rft.pages=e1008778-e1008778&rft.issn=1553-7374&rft.eissn=1553-7374&rft_id=info:doi/10.1371/journal.ppat.1008778&rft_dat=%3Cgale_plos_%3EA634243376%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2443613469&rft_id=info:pmid/32841292&rft_galeid=A634243376&rft_doaj_id=oai_doaj_org_article_993b404646e449dda04d3ca0423c8dbe&rfr_iscdi=true |