{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:34:38Z","timestamp":1792622078605,"version":"4.5.0"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T00:00:00Z","timestamp":1584662400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16H05412"],"award-info":[{"award-number":["16H05412"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19H03726"],"award-info":[{"award-number":["19H03726"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19ck0106263h0003"],"award-info":[{"award-number":["19ck0106263h0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19cm0106510h0004"],"award-info":[{"award-number":["19cm0106510h0004"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Epstein\u2010Barr virus (EBV) is associated with particular forms of gastric cancer (GC). We previously showed that EBV infection into gastric epithelial cells induced aberrant DNA hypermethylation in promoter regions and silencing of tumor suppressor genes. We here undertook integrated analyses of transcriptome and epigenome alteration during EBV infection in gastric cells, to investigate activation of enhancer regions and related transcription factors (TFs) that could contribute to tumorigenesis. Formaldehyde\u2010assisted isolation of regulatory elements (FAIRE) sequencing (\u2010seq) data revealed 19\u00a0992 open chromatin regions in putative H3K4me1<jats:sup>+<\/jats:sup> H3K4me3<jats:sup>\u2212<\/jats:sup> enhancers in EBV\u2010infected MKN7 cells (MKN7_EB), with 10\u00a0260 regions showing increase of H3K27ac. Motif analysis showed candidate TFs, eg activating transcription factor 3 (ATF3), to possibly bind to these activated enhancers. ATF3 was considerably upregulated in MKN7_EB due to EBV factors including EBV\u2010determined nuclear antigen 1 (EBNA1), EBV\u2010encoded RNA 1, and latent membrane protein 2A. Expression of mutant EBNA1 decreased copy number of the EBV genome, resulting in relative downregulation of <jats:italic>ATF3<\/jats:italic> expression. Epstein\u2010Barr virus was also infected into normal gastric epithelial cells, GES1, confirming upregulation of <jats:italic>ATF3<\/jats:italic>. Chromatin immunoprecipitation\u2010seq analysis on ATF3 binding sites and RNA\u2010seq analysis on ATF3 knocked\u2010down MKN7_EB revealed 96 genes targeted by ATF3\u2010activating enhancers, which are related with cancer hallmarks, eg evading growth suppressors. These 96 ATF3 target genes were significantly upregulated in MKN7_EB compared with MKN7 and significantly downregulated when ATF3 was knocked down in EBV\u2010positive GC cells SNU719 and NCC24. Knockdown of ATF3 in EBV\u2010infected MKN7, SNU719, and NCC24 cells all led to significant decrease of cellular growth through an increase of apoptotic cells. These indicate that enhancer activation though ATF3 might contribute to tumorigenesis of EBV\u2010positive GC.<\/jats:p>","DOI":"10.1111\/cas.14370","type":"journal-article","created":{"date-parts":[[2020,3,2]],"date-time":"2020-03-02T15:35:57Z","timestamp":1583163357000},"page":"1818-1828","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Epstein\u2010Barr virus\u2010positive gastric cancer involves enhancer activation through activating transcription factor 3"],"prefix":"10.1111","volume":"111","author":[{"given":"Yuta","family":"Asakawa","sequence":"first","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Okabe","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Fukuyo","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"},{"name":"Department of Genome Research and Development Kazusa DNA Research Institute Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhe","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eriko","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunobu","family":"Mano","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Funata","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroe","family":"Namba","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"},{"name":"School of Medicine Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuko","family":"Kita","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Matsusaka","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"},{"name":"Department of Pathology Chiba University Hospital Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6980-5515","authenticated-orcid":false,"given":"Atsushi","family":"Kaneda","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,3,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31937"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.09.004"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa001999"},{"key":"e_1_2_9_5_1","first-page":"769","article-title":"Epstein\u2010Barr virus\u2010associated gastric adenocarcinoma","volume":"140","author":"Shibata D","year":"1992","journal-title":"Am J Pathol"},{"key":"e_1_2_9_6_1","first-page":"377","article-title":"Lymphoepithelial carcinoma of the stomach with Epstein\u2010Barr virus demonstrated by polymerase chain reaction","volume":"3","author":"Burke AP","year":"1990","journal-title":"Mod Pathol"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.05.001"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002878"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13480"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/310207a0"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.92"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2008.00888.x"},{"key":"e_1_2_9_13_1","first-page":"7062","article-title":"Autocrine growth of Epstein\u2010Barr virus\u2010positive gastric carcinoma cells mediated by an Epstein\u2010Barr virus\u2010encoded small RNA","volume":"63","author":"Iwakiri D","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-1349"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4909"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2016.202"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.02.033"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.12.013"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.06.018"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08370-7"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19423"},{"key":"e_1_2_9_22_1","first-page":"869","article-title":"Overexpression of activating transcription factor 3 exerts suppressive effects in HepG2 cells","volume":"19","author":"Li X","year":"2019","journal-title":"Mol Med Rep"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2018.08.107"},{"key":"e_1_2_9_24_1","first-page":"7","article-title":"Establishment and characterization of a SV40 transformed human fetal gastric epithelial cell line\u2010GES\u20101","volume":"16","author":"Ke Y","year":"1994","journal-title":"Zhonghua Zhong Liu Za Zhi"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.5.4371-4378.1998"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002359"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.004"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13130"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.71.3.1766-1775.1997"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.11.002"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02318-15"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-7-262"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-016-2664-8"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-0466"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.426"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2015.08.086"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-1842"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64410"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0943"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.064915"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-014-2796-x"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.2008\/003392-0"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0147-x"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210496"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcas.14370","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.14370","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cas.14370","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.14370","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T10:05:09Z","timestamp":1708941909000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.14370"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,20]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,5]]}},"alternative-id":["10.1111\/cas.14370"],"URL":"https:\/\/doi.org\/10.1111\/cas.14370","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,20]]},"assertion":[{"value":"2019-12-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}