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DNA methyltransferase 2 (DNMT2) regulates the m5C methylation status of tRNA, thereby reprogramming its structure and influencing cancer progression. However, the precise mechanisms through which DNMT2 affects tumor development via tRNA methylation remain insufficiently understood. In this study, we demonstrate that reduced DNMT2 expression promotes the progression of anaplastic thyroid carcinoma (ATC). Specifically, in ATC, DNMT2 catalyzes m5C38 methylation on three tRNAs: tRNA-Asp-GUC, tRNA-Gly-GCC, and tRNA-Val-AAC. Loss of DNMT2 leads to an increased abundance of 5\u2019tiRNA\n                    <jats:sup>Gly-GCC<\/jats:sup>\n                    , generated by ANG-mediated cleavage of m5C38-hypomethylated tRNA-Gly-GCC. This 5\u2019tiRNA\n                    <jats:sup>Gly-GCC<\/jats:sup>\n                    directly binds to hnRNPH1, resulting in a reduction of its protein levels. Moreover, combined treatment with a 5\u2019tiRNA\n                    <jats:sup>Gly-GCC<\/jats:sup>\n                    inhibitor and doxorubicin hydrochloride significantly suppresses ATC progression in vivo. Thus, decreased DNMT2 expression facilitates ATC development by promoting the production of 5\u2019tiRNA\n                    <jats:sup>Gly-GCC<\/jats:sup>\n                    . Our findings also highlight the considerable therapeutic potential of targeting 5\u2019tiRNA\n                    <jats:sup>Gly-GCC<\/jats:sup>\n                    in the treatment of ATC.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08488-5","type":"journal-article","created":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T08:16:55Z","timestamp":1771661815000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["DNMT2 inhibits anaplastic thyroid cancer progression by downregulating 5\u2019tiRNAGly-GCC production"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7985-5260","authenticated-orcid":false,"given":"Ruixin","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7049-5511","authenticated-orcid":false,"given":"Baizhao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9435-8843","authenticated-orcid":false,"given":"Zhijing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8904-897X","authenticated-orcid":false,"given":"Fada","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9786-2497","authenticated-orcid":false,"given":"Xinying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,21]]},"reference":[{"key":"8488_CR1","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1186\/s13046-019-1198-8","volume":"38","author":"M Mazzoni","year":"2019","unstructured":"Mazzoni M, Mauro G, Erreni M, Romeo P, Minna E, Vizioli MG, et al. 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Mol Cancer. 2024;23:76.","journal-title":"Mol Cancer"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08488-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08488-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08488-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T14:02:59Z","timestamp":1772200979000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08488-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,21]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8488"],"URL":"https:\/\/doi.org\/10.1038\/s41419-026-08488-5","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,21]]},"assertion":[{"value":"11 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 January 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 February 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 February 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This research is approved by the Animal Welfare and Ethics Committee of Xiangya Hospital, Central South University (No. XY20240228008) and Xiangya Hospital\u2019s Protection of Human Subjects Committee (No. 202004192) with informed consent from patients. The maximum allowed tumor size\/burden was 1500 mm\n                      3\n                      , as approved by the ethics committee. We confirm that the maximal tumor size was not exceeded in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"240"}}