Xinying Li

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.

Persistent and intense endoplasmic reticulum (ER) stress is widely acknowledged as a hallmark of tumorigenesis. To restore ER homeostasis, cells activate the unfolded protein response (UPR), which is aberrantly regulated in cancer cells. This review provides an in‐depth analysis of the mechanisms through which the UPR facilitates tumor progression. The UPR is activated by ER stress sensors such as inositol‐requiring enzyme 1 (IRE1α), protein kinase R‐like ER‐resident kinase (PERK), and activating transcription factor 6 (ATF6). These sensors regulate cancer cell proliferation, immune evasion, metastasis, and drug resistance. We summarize the crosstalk between the UPR and multiple signaling pathways, including mTOR, MAPK, and NF‐κB, which collectively promote tumor growth and metastasis. Additionally, we discuss the role of the UPR in modulating the tumor microenvironment to support angiogenesis and immune evasion. We also provide an overview of pharmacological agents targeting specific UPR pathways, such as GRP78 inhibitors, IRE1α inhibitors, PERK inhibitors, and ATF6 inhibitors, with the aim of developing more effective cancer therapies. This comprehensive review highlights the potential of targeting the UPR as a novel strategy for cancer treatment and underscores the need for further research to elucidate the complex interactions between the UPR and cancer progression.

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.

Background: Translation dysregulation plays a crucial role in tumourigenesis and cancer progression. Oncogenic translation relies on the stability and availability of tRNAs for protein synthesis, making them potential targets for cancer therapy.Methods: This study performed immunohistochemistry analysis to assess NSUN2 levels in thyroid cancer. Furthermore, to elucidate the impact of NSUN2 on anaplastic thyroid cancer (ATC) malignancy, phenotypic assays were conducted. Drug inhibition and time‐dependent plots were employed to analyse drug resistance. Liquid chromatography–mass spectrometry and bisulphite sequencing were used to investigate the m⁵C methylation of tRNA at both global and single‐base levels. Puromycin intake and high‐frequency codon reporter assays verified the protein translation level. By combining mRNA and ribosome profiling, a series of downstream proteins and codon usage bias were identified. The acquired data were further validated by tRNA sequencing.Results: This study observed that the tRNA m⁵C methyltransferase NSUN2 was up‐regulated in ATC and is associated with dedifferentiation. Furthermore, NSUN2 knockdown repressed ATC formation, proliferation, invasion and migration both in vivo and in vitro. Moreover, NSUN2 repression enhanced the sensitivity of ATC to genotoxic drugs. Mechanically, NSUN2 catalyses tRNA structure‐related m⁵C modification, stabilising tRNA that maintains homeostasis and rapidly transports amino acids, particularly leucine. This stable tRNA has a substantially increased efficiency necessary to support a pro‐cancer translation program including c‐Myc, BCL2, RAB31, JUNB and TRAF2. Additionally, the NSUN2‐mediated variations in m5C levels and different tRNA Leu iso‐decoder families, partially contribute to a codon‐dependent translation bias. Surprisingly, targeting NSUN2 disrupted the c‐Myc to NSUN2 cycle in ATC.Conclusions: This research revealed that a pro‐tumour m5C methyltransferase, dynamic tRNA stability regulation and downstream oncogenes, c‐Myc, elicits a codon‐dependent oncogenic translation network that enhances ATC growth and formation. Furthermore, it provides new opportunities for targeting translation reprogramming in cancer cells.

Background: The current TNM classification that simply classifies differentiated thyroid carcinoma (DTC) patients younger than 55 years into stage I and stage II based on the presence or absence of distant metastases has been questioned. In this study, we reexamined the impact of T status and N status on prognosis and then developed a new prediction model to improve the predictability of cancer-specific survival (CSS) in young patients.Materials and methods: Kaplan–Meier method was applied to calculate the CSS. Multivariable Cox proportional hazards models were used to assess the impact of T status and N status on CSS after adjustment for known covariates. The area under the receiver operating characteristic curve (AUC), C-index, Bayesian information criterion (BIC), and Akaike information criterion (AIC) were calculated to compare model performance.Results: A total of 9,242 DTC patients younger than 55 years were enrolled in the study. After adjusting for gender, age at diagnosis, race, pathology subtype, N stage, and M stage, T3 disease [hazard ratio (HR): 3.78, P = 0.006] and T4 disease (HR: 7.96, P < 0.001) remain independent predictors of CSS. Similarly, the 10-year CSS rate of N1b disease (HR: 3.78, P < 0.001) was significantly higher than that of N0 disease after adjustment. Moreover, Kaplan–Meier survival analysis showed that the 10-year CSS of stage II disease in younger patients with DTC showed a sharp decrease compared with that in older patients with DTC (74.47% vs. 98.43%, P < 0.001). Furthermore, a modified TNM staging system based on significantly prognostic T stage and N stage was established, which showed better performance than the current TNM staging system (P < 0.05). The new prediction model is also applicable to papillary thyroid carcinoma patients and follicular thyroid carcinoma patients.Conclusions: This is the first study to question the rationality of the current TNM staging system for patients younger than 55 years and successfully develop a new prognostic model, which improves prognostic stratification and guides individualized management.

Dedifferentiation is the main concern associated with radioactive iodine (RAI) refractoriness in patients with papillary thyroid cancer (PTC), and the underlying mechanisms of PTC dedifferentiation remain unclear. The present work aimed to identify a useful signature to indicate dedifferentiation and further explore its role in prognosis and susceptibility to chemotherapy drugs. A total of five prognostic-related DR-lncRNAs were selected to establish a prognostic-predicting model, and corresponding risk scores were closely associated with the infiltration of immune cells and immune checkpoint blockade. Moreover, we built an integrated nomogram based on DR-lncRNAs and age that showed a strong ability to predict the 3- and 5-year overall survival. Interestingly, drug sensitivity analysis revealed that the low-risk group was more sensitive to Bendamustine and TAS-6417 than the high-risk group. In addition, knockdown of DR-lncRNAs (DPH6-DT) strongly promoted cell proliferation, invasion, and migration via PI3K-AKT signal pathway in vitro. Furthermore, DPH6-DT downregulation also increased the expression of vimentin and N-cadherin during epithelial-mesenchymal transition. This study firstly confirms that DR-lncRNAs play a vital role in the prognosis and immune cells infiltration in patients with PTC, as well as a predictor of the drugs’ chemosensitivity. Based on our results, DR-lncRNAs can serve as a promising prognostic biomarkers and treatment targets.