NSUN2-mediated RNA 5-methylcytosine promotes esophageal squamous cell carcinoma progression via LIN28B-dependent GRB2 mRNA stabilization
Jiachun Su, Guandi Wu, Ying Ye, Jialiang Zhang, Lingxing Zeng, Xudong Huang, Yanfen Zheng, Ruihong Bai, Lisha Zhuang, Mei Li, Ling Pan, Junge Deng, Rui Li, Shuang Deng, Shaoping Zhang, Zhixiang Zuo, Zexian Liu, Junzhong Lin, Dongxin Lin, Jian Zheng
Abstract
Abstract 5-Methylcytosine (m 5 C) is a posttranscriptional RNA modification participating in many critical bioprocesses, but its functions in human cancer remain unclear. Here, by detecting the transcriptome-wide m 5 C profiling in esophageal squamous cell carcinoma (ESCC), we showed increased m 5 C methylation in ESCC tumors due to the overexpressed m 5 C 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 m 5 C modification of growth factor receptor-bound protein 2 ( GRB2 ) and stabilized its mRNA, which was mediated by a novel m 5 C 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 m 5 C-LIN28B dependent stabilization of GRB2 transcript, providing a promising epitranscriptomic-targeted therapeutic strategy for ESCC.