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EBV-encoded nuclear antigen 1 (EBNA1) is uniformly expressed in EBV-associated cancers; however, how EBNA1 contributes to cancer progression is not known. The <jats:italic>MUC1<\/jats:italic> gene evolved in mammals to protect barrier tissues from viral infections. We report that <jats:italic>MUC1<\/jats:italic> is upregulated in EBV-associated gastric cancers (EBVaGCs). Our results demonstrate that EBNA1 and the oncogenic MUC1-C subunit form an auto-regulatory complex that controls expression of EBNA1, MUC1-C and host cellular genes. EBNA1 appropriates MUC1-C to (i) induce DNA methyltransferase (DNMT) expression and DNA methylation, (ii) suppress <jats:italic>CDKN1A<\/jats:italic> encoding p21 to promote proliferation, and (iii) upregulate survivin to confer survival. MUC1-C is also co-opted for localization of EBNA1 in chromatin, expression of EBV latency genes and suppression of lytic genes. Targeting MUC1-C thereby induces the switch of EBV latency to activation of the lytic phase. We further demonstrate that MUC1-C is necessary for EBVaGC stem cell (CSC) state as evidenced by regulation of NOTCH stemness genes and self-renewal capacity. These findings and the demonstration that EBV positivity has no significant effect on survival of patients with GCs indicate that EBNA1 exploits MUC1-C to maintain EBV latency and that prolonged activation of MUC1-C in response to chronic EBV infection promotes EBVaGC malignant progression.<\/jats:p>","DOI":"10.1038\/s41388-025-03519-5","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T07:37:40Z","timestamp":1754379460000},"page":"3609-3624","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["MUC1-C auto-regulatory complex with EBNA1 is responsible for latent Epstein-Barr virus-associated gastric cancer progression"],"prefix":"10.1038","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3771-7940","authenticated-orcid":false,"given":"Hiroki","family":"Ozawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9746-9352","authenticated-orcid":false,"given":"Henry G.","family":"Withers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Haratake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Nakashoji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atrayee","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Fushimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chie","family":"Kikutake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Yamanoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaowen","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5656-2115","authenticated-orcid":false,"given":"Keyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuaki","family":"Daimon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Shigeta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumasa","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Kawakubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Kitagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1120-8176","authenticated-orcid":false,"given":"Mark D.","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin E.","family":"Gewurz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5743-8888","authenticated-orcid":false,"given":"Donald","family":"Kufe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"3519_CR1","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/S0140-6736(64)92354-2","volume":"1","author":"MA Epstein","year":"1964","unstructured":"Epstein MA, Barr YM. 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