DNMT2 inhibits anaplastic thyroid cancer progression by downregulating 5’tiRNAGly-GCC production

Complex tRNA methylation modifications collectively maintain the structural integrity and functional efficiency of tRNA. 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'tiRNA^Gly-GCC, generated by ANG-mediated cleavage of m5C38-hypomethylated tRNA-Gly-GCC. This 5'tiRNA^Gly-GCC directly binds to hnRNPH1, resulting in a reduction of its protein levels. Moreover, combined treatment with a 5'tiRNA^Gly-GCC inhibitor and doxorubicin hydrochloride significantly suppresses ATC progression in vivo. Thus, decreased DNMT2 expression facilitates ATC development by promoting the production of 5'tiRNA^Gly-GCC. Our findings also highlight the considerable therapeutic potential of targeting 5'tiRNA^Gly-GCC in the treatment of ATC.