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Therefore, identifying the pathways that contribute to chemoresistance may show new possibilities for improving the treatment. This work explored the role of the tumor necrosis factor\u2010alpha (TNF\u2010alpha)\/NFkB signaling in driving the cisplatin resistance of OSCC and its potential as a pharmacological target to overcome chemoresistance. Differential accessibility analysis demonstrated the enrichment of opened chromatin regions in members of the TNF\u2010alpha\/NFkB signaling pathway, and RNA\u2010Seq confirmed the upregulation of TNF\u2010alpha\/NFkB signaling in cisplatin\u2010resistant cell lines. NFkB was accumulated in cisplatin\u2010resistant cell lines and in cancer stem cells (CSC), and the administration of TNF\u2010alpha increased the CSC, suggesting that TNF\u2010alpha\/NFkB signaling is involved in the accumulation of CSC. TNF\u2010alpha stimulation also increased the histone deacetylases HDAC1 and SIRT1. Cisplatin\u2010resistant cell lines were sensitive to the pharmacological inhibition of NFkB, and low doses of the NFkB inhibitors, CBL0137, and emetine, efficiently reduced the CSC and the levels of SIRT1, increasing histone acetylation. The NFkB inhibitors decreased stemness potential, clonogenicity, migration, and invasion of cisplatin\u2010resistant cell lines. The administration of the emetine significantly reduced the tumor growth of cisplatin\u2010resistant xenograft models, decreasing NFkB and SIRT1, increasing histone acetylation, and decreasing CSC. TNF\u2010alpha\/NFkB\/SIRT1 signaling regulates the epigenetic machinery by modulating histone acetylation, CSC, and aggressiveness of cisplatin\u2010resistant OSCC and the NFkB inhibition is a potential strategy to treat chemoresistant OSCC.<\/jats:p>","DOI":"10.1002\/jcp.31164","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T13:19:45Z","timestamp":1703683185000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Up\u2010regulation of TNF\u2010alpha\/NFkB\/SIRT1 axis drives aggressiveness and cancer stem cells accumulation in chemoresistant oral squamous cell carcinoma"],"prefix":"10.1002","volume":"239","author":[{"given":"Let\u00edcia Rodrigues","family":"de Castro","sequence":"first","affiliation":[{"name":"Department of Basic and Oral Biology School of Dentistry of Ribeir\u00e3o Preto, University of S\u00e3o Paulo Ribeir\u00e3o Preto S\u00e3o Paulo 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