Abstract5-Methylcytosine (m5C) is a posttranscriptional RNA modification participating in many critical bioprocesses, but its functions in human cancer remain unclear. Here, by detecting the transcriptome-wide m5C profiling in esophageal squamous cell carcinoma (ESCC), we showed increased m5C methylation in ESCC tumors due to the overexpressed m5C methyltransferase NSUN2. Aberrant expression of NSUN2 was positively regulated by E2F Transcription Factor 1 (E2F1). High NSUN2 levels predicted poor survival of ESCC patients. Moreover, silencing NSUN2 suppressed ESCC tumorigenesis and progression in Nsun2 knockout mouse models. Mechanistically, NSUN2 induced m5C modification of growth factor receptor-bound protein 2 (GRB2) and stabilized its mRNA, which was mediated by a novel m5C mediator, protein lin-28 homolog B (LIN28B). Elevated GRB2 levels increased the activation of PI3K/AKT and ERK/MAPK signalling. These results demonstrate that NSUN2 enhances the initiation and progression of ESCC via m5C-LIN28B dependent stabilization of GRB2 transcript, providing a promising epitranscriptomic-targeted therapeutic strategy for ESCC.

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AMT, 4'-aminomethyltrioxalen; ChIRP, chromatin isolation by RNA purification; CIMS, cross-linking induced mutation sites; CITS, crosslinking-induced truncation sites; CNBP, CCHC-type zinc finger nucleic acid binding protein; EMSA, electrophoretic mobility shift assay; FISH, fluorescent in situ hybridization; lncRNA, long non-coding RNA; m 6 A, N 6 -methyladenosine; MeRIP, m 6 A-specific RNA immunoprecipitation; miCLIP, m 6 A individual-nucleotide resolution cross-linking and immunoprecipitation; PDAC, pancreatic ductal adenocarcinoma; PDX, patient-derived xenograft; RIP, RNA immunoprecipitation; sgRNA, small guide RNA; siRNA, small interfering RNA; WTAP, WT1 associated protein.Research.

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