{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:56:58Z","timestamp":1785427018078,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRIN","award":["2022LNHZAP_002"],"award-info":[{"award-number":["2022LNHZAP_002"]}]},{"name":"AIRC","award":["IG2019-23040"],"award-info":[{"award-number":["IG2019-23040"]}]},{"award":["IG2019-23040"],"award-info":[{"award-number":["IG2019-23040"]}],"id":[{"id":"https:\/\/ror.org\/02g2x7380","id-type":"ROR","asserted-by":"publisher"}]},{"name":"ATENEO","award":["2024"],"award-info":[{"award-number":["2024"]}]},{"award":["2024"],"award-info":[{"award-number":["2024"]}],"id":[{"id":"https:\/\/ror.org\/053kevk63","id-type":"ROR","asserted-by":"publisher"}]},{"name":"ATENEO","award":["2025"],"award-info":[{"award-number":["2025"]}]},{"award":["2025"],"award-info":[{"award-number":["2025"]}],"id":[{"id":"https:\/\/ror.org\/053kevk63","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>We previously demonstrated that human herpesvirus 6A infects papillary thyroid cancer cells (BCPAP), inducing molecular changes compatible with a tumor-promoting phenotype, including increased expression of R273H mutant TP53 (mutp53), upregulation of c-Myc, and enhanced secretion of IL-6. To investigate whether and how epigenetic mechanisms contribute to these virus-induced effects, we examined the histone methyltransferase EZH2, a key regulator of chromatin repression frequently altered in cancer. HHV-6A infection reduced EZH2 expression and global H3K27me3 levels. Pharmacological inhibition of EZH2 using DS-3201 reproduced some of the molecular effects of viral infection, including increased mutp53 stability. Both viral infection and EZH2 inhibition induced delayed upregulation of SIRT1, which mediated deacetylation-dependent stabilization of mutp53 while reducing c-Myc expression. Indeed, the inhibition of SIRT1 with EX-527 reversed mutp53 accumulation but restored c-Myc expression and increased extracellular IL-6 release. This drug also reduced cell survival, suggesting that SIRT1 supports cellular adaptation to oncogenic stress triggered by EZH2 loss. Overall, our findings identify an epigenetic axis in which the HHV-6A-mediated downregulation of EZH2 induces SIRT1, regulating mutp53 stability and c-Myc expression and reshaping inflammatory signaling to maintain cell viability. These results establish a mechanistic link between viral infection, epigenetic remodeling, and oncogenic dependency. They also suggest that targeting IL-6 signaling could represent a therapeutic vulnerability in HHV-6A-associated thyroid cancer, particularly in combination with SIRT1 inhibitors.<\/jats:p>","DOI":"10.3390\/v18040409","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:36:40Z","timestamp":1774532200000},"page":"409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HHV-6A Drives Epigenetic Reprogramming via an EZH2\u2013SIRT1 Axis to Sustain Mutant p53 and Reshape Oncogenic Inflammatory Signaling"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1825-9112","authenticated-orcid":false,"given":"Rossella","family":"Benedetti","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4085-8350","authenticated-orcid":false,"given":"Michele","family":"Di Crosta","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Stirparo","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George Alexandru","family":"Aron","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9032-9667","authenticated-orcid":false,"given":"Stefania","family":"Mardente","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9416-7594","authenticated-orcid":false,"given":"Roberta","family":"Santarelli","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4894-4986","authenticated-orcid":false,"given":"Roberta","family":"Gonnella","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8722-7539","authenticated-orcid":false,"given":"Maria Saveria","family":"Gilardini Montani","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2207-9624","authenticated-orcid":false,"given":"Mara","family":"Cirone","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1080\/17501911.2024.2415282","article-title":"Altered epigenetic landscape as infectious disease diagnostics","volume":"16","author":"Spurbeck","year":"2024","journal-title":"Epigenomics"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bautista, J., and Lopez-Cortes, A. 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