Zhijing Wu

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.

Purpose: This retrospective cohort study aimed to reevaluate the prognostic impact of sex and determine whether age modifies the effect of sex on cancer-specific survival (CSS) in PTC patients. Methods: Data for PTC patients diagnosed between 2004 and 2015 were retrieved from the SEER database. The primary outcome was CSS. The effect of Sex was evaluated using both relative (hazard ratios, HRs) and absolute measures (survival differences). Additionally, the effect of sex modified by age was assessed using restricted cubic spline curves from the Cox and Poisson models, with further analysis of the interaction between sex and age. Results: Of 77,349 patients, 16,152 (20.9%) were male. Men exhibited older age, more aggressive clinicopathological features, and received more radioactive iodine treatment. Multivariate Cox analysis determined male sex as an independent risk factor (adjusted HR: 1.46 (1.24–1.70). The 10-year and 15-year survival differences between men and women were 0.46% (95% CI, 0.25%−0.67%) and 0.77% (95% CI, 0.31%−1.22%), respectively. Moreover, a nonlinear effect for sex across age was observed, with HRs for men plateauing below age 50 and decreasing thereafter. Importantly and conversely, before age 50, the absolute survival difference increased slightly with age, but after 50, it significantly widened. Furthermore, A significant negative multiplicative interaction between sex and age was found. Conclusions: Our analyses provide robust evidence that male sex is indeed an independent risk factor for CSS in PTC patients. Although younger female patients show a relative survival advantage, this does not translate into a substantial absolute benefit, which widens with advancing age.

High‐throughput sequencing has sparked increased research interest in RNA modifications, particularly tRNA methylation, and its connection to various diseases. However, the precise mechanisms underpinning the development of these diseases remain largely elusive. This review sheds light on the roles of several tRNA methylations (m1A, m3C, m5C, m1G, m2G, m7G, m5U, and Nm) in diverse biological functions, including metabolic processing, stability, protein interactions, and mitochondrial activities. It further outlines diseases linked to aberrant tRNA modifications, related enzymes, and potential underlying mechanisms. Moreover, disruptions in tRNA regulation and abnormalities in tRNA‐derived small RNAs (tsRNAs) contribute to disease pathogenesis, highlighting their potential as biomarkers for disease diagnosis. The review also delves into the exploration of drugs development targeting tRNA methylation enzymes, emphasizing the therapeutic prospects of modulating these processes. Continued research is imperative for a comprehensive comprehension and integration of these molecular mechanisms in disease diagnosis and treatment.