N4-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma

Journal of Experimental & Clinical Cancer Research, Год журнала: 2025, Номер 44(1)

Опубликована: Март 22, 2025

Abstract Background Perineural invasion (PNI) is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC), which occurs at high incidence and significantly contributes to PDAC lethality poor survival. Despite its prevalence association with prognosis, the molecular mechanisms underlying PNI in remain unclear. Methods We investigated clinical samples from two cohorts by UPLC/MS-MS profiled altered chemical RNA modifications tissues lesions. Dorsal root ganglion coculture systems sciatic nerve injection models validated ability. combined RNA-seq, acRIP-seq ac4C-seq CRISPR-based techniques explore regulatory mechanism ac4C modification on integrin beta 5 ( ITGB5 ) transcript. Result reported that N 4 -acetylcytidine (ac4C) In vitro vivo demonstrated tumor cells overexpression N-acetyltransferase 10 (NAT10), writer enzyme mRNA modification, enhances PDAC. Further analysis revealed decreased levels transcripts focal adhesion pathway, particular ITGB5, NAT10-knockdown cells. This CDS region promotes stability, subsequently activating ITGB5-pFAK-pSrc pathway. further confirmed crucial role NAT10-mediated regulating expression. Combining small-molecule inhibitors targeting NAT10 kinase (FAK) attenuated vivo. Conclusion Our findings reveal previously unrecognized ac4C-mediated epigenetic propose novel therapeutic strategy improve survival patients. One-sentence summary via

Язык: Английский

---

Epitranscriptomic modifications in mesenchymal stem cell differentiation: advances, mechanistic insights, and beyond

Cell Death and Differentiation, Год журнала: 2023, Номер 31(1), С. 9 - 27

Опубликована: Ноя. 20, 2023

Язык: Английский

---

TRMT10A dysfunction perturbs codon translation of initiator methionine and glutamine and impairs brain functions in mice

Nucleic Acids Research, Год журнала: 2024, Номер 52(15), С. 9230 - 9246

Опубликована: Июль 2, 2024

Abstract In higher eukaryotes, tRNA methyltransferase 10A (TRMT10A) is responsible for N1-methylguanosine modification at position nine of various cytoplasmic tRNAs. Pathogenic mutations in TRMT10A cause intellectual disability, microcephaly, diabetes, and short stature humans, generate cytotoxic fragments cultured cells; however, it not clear how supports codon translation or brain functions. Here, we generated Trmt10a null mice showed that tRNAGln(CUG) initiator methionine levels were universally decreased tissues; the same was true a human cell line lacking TRMT10A. Ribosome profiling mouse revealed dysfunction causes ribosome slowdown Gln(CAG) increases Atf4 due to frequency leaky scanning its upstream open reading frames. Broadly speaking, subset mRNAs, especially those neuronal structures, perturbed mutant brain. Despite showing discernable defects pancreas, liver, kidney, lower body weight smaller hippocampal postsynaptic densities, which associated with defective synaptic plasticity memory. Taken together, our study provides mechanistic insight into roles brain, exemplifies importance universal during specific codons.

Язык: Английский

---

NAT10 promotes vascular remodelling via mRNA ac4C acetylation

European Heart Journal, Год журнала: 2024, Номер unknown

Опубликована: Окт. 25, 2024

Vascular smooth muscle cell (VSMC) phenotype switching is a pathological hallmark in various cardiovascular diseases. N4-acetylcytidine (ac4C) catalyzed by N-acetyltransferase 10 (NAT10) well conserved the enzymatic modification of ribonucleic acid (RNA). NAT10-mediated ac4C acetylation involved physiological and processes, including cardiac remodelling. However, biological functions underlying regulatory mechanisms mRNA modifications vascular diseases remain elusive.

Язык: Английский

---

Single-cell and spatial transcriptomics: Bridging current technologies with long-read sequencing

Molecular Aspects of Medicine, Год журнала: 2024, Номер 96, С. 101255 - 101255

Опубликована: Фев. 17, 2024

Язык: Английский

---