NSUN2-mediated RNA 5-methylcytosine promotes esophageal squamous cell carcinoma progression via LIN28B-dependent GRB2 mRNA stabilization

Abstract

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.

UHRF1, NSUN2, and NEIL1 were Detected as Clinical Biomarker Candidates in Prostate Adenocarcinoma with Potential Roles in Disease Pathogenesis

“…A similar association with cancer progression has been also described for NSUN2 overexpression. High expression of NSUN2 was linked to the development of several cancers such as esophageal squamous cell carcinoma (ESCC) [92], gastric cancer [79], and hypopharyngeal squamous cell carcinoma and [93]. Since our results indicated the high mRNA expression level as the most commonly detected alteration of UHRF1 and NSUN2 genes in PRAD patients, the obtained cell cycle-related BPs for the altered group of UHRF1 and NSUN2 strongly favors the findings of previously conducted studies.…”

Roles of m5C RNA Modification Patterns in Biochemical Recurrence and Tumor Microenvironment Characterization of Prostate Adenocarcinoma

“…Owing to the advance in detection technologies, accumulating research has verified that m5C modification played a key role in the post-transcriptional modification of gene expression, which was closely related to tumor formation, maintenance, and progression ( 10 , 51 , 52 ). As reported, the m5C writer NSUN2 was proven to stabilize the GRB2 mRNA via m5C dependent manner in esophageal cancer ( 53 ). Some studies have validated that m5C modification played an important role in bladder cancer progression via modulating the stabilization of mRNA ( 6 , 12 ).…”

NSUN2-mediated mRNA m5C Modification Regulates the Progression of Hepatocellular Carcinoma

“…Li et al showed that NSUN2 coordinates with lin-28B, a novel m 5 C recognition protein, to catalyze the m 5 C modification of GRB2 and stabilize its mRNA expression. High levels of GRB2 promote the activation of the PI3K/AKT and Ras pathways in esophageal squamous cell carcinoma [30]. We demonstrated that NSUN2 inhibited the Ras activation and decreased the p-ErK level in HCC, which led to the increased sensitivity of HCC cells to sorafenib.…”