{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T08:50:08Z","timestamp":1785747008095,"version":"3.56.0"},"reference-count":38,"publisher":"OAE Publishing Inc.","content-domain":{"domain":["oaepublish.com"],"crossmark-restriction":false},"short-container-title":["Cancer Drug Resist."],"abstract":"<jats:p>Aim: This study investigates the role of Ten-Eleven Translocation (TET) dioxygenases in melanoma-acquired resistance to BRAF inhibitors (BRAFi), focusing on their contributions to epigenetic remodeling and redox balance.<\/jats:p>\n                  <jats:p>Methods: Dabrafenib-resistant A375 and M14 melanoma cell lines were generated and analyzed for TET family expression. Transcriptomic data from independent RNA-seq datasets of BRAFi-resistant melanoma models were used for validation. Cells were treated with high-dose L-ascorbic acid (ASC), a cofactor enhancing TET activity, and assessed for 5-hydroxymethylcytosine (5hmC) levels, reactive oxygen species (ROS) production, and cytotoxicity. Antioxidant capacity and expression of GLUT1, a transporter for oxidized ASC, were evaluated. TET2 was silenced to determine its functional role in ASC-mediated effects.<\/jats:p>\n                  <jats:p>Results: BRAFi-resistant cells displayed reduced TET2 expression and altered levels of other TET family members, consistent with RNA-seq data. ASC treatment increased 5hmC levels and induced ROS-dependent cytotoxicity predominantly in parental cells, while resistant cells were less sensitive. Resistant cells exhibited enhanced antioxidant defenses and reduced GLUT1 expression. TET2 silencing diminished ASC-induced 5hmC accumulation, ROS production, and GLUT1 expression, indicating a central role for TET2 in mediating ASC cytotoxicity.<\/jats:p>\n                  <jats:p>Conclusion: These findings identify a TET2-dependent epigenetic\u2013metabolic axis that regulates redox vulnerability in melanoma. The link between TET2 activity, GLUT1 expression, and ROS-mediated cytotoxicity highlights potential biomarkers and therapeutic targets to overcome resistance to BRAFi.<\/jats:p>","DOI":"10.20517\/cdr.2026.42","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T08:41:43Z","timestamp":1785746503000},"update-policy":"https:\/\/doi.org\/10.20517\/oae.crossmark.policy","source":"Crossref","is-referenced-by-count":0,"title":["TET2 downregulation limits oxidative stress-induced cytotoxicity of high dose ascorbate in dabrafenib-resistant melanoma cells"],"prefix":"10.20517","author":[{"given":"Eleicy Nathaly","family":"Mendoza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Castelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"De 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