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

• Published in: Oncogene Vol. 40; no. 39; pp. 5814 - 5828
• Main Authors: Su, Jiachun, Wu, Guandi, Ye, Ying, Zhang, Jialiang, Zeng, Lingxing, Huang, Xudong, Zheng, Yanfen, Bai, Ruihong, Zhuang, Lisha, Li, Mei, Pan, Ling, Deng, Junge, Li, Rui, Deng, Shuang, Zhang, Shaoping, Zuo, Zhixiang, Liu, Zexian, Lin, Junzhong, Lin, Dongxin, Zheng, Jian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.09.2021; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/109; 13/51; 13/89; 38/39; 38/90; 38/91; 5-Methylcytosine - analogs & derivatives; 5-Methylcytosine - metabolism; 631/337/1645; 631/337/176; 631/67/1504/1477; 64/110; 82/58; AKT protein; Animal models; Animals; Apoptosis; Cancer; Cell Biology; Cell Line, Tumor; Development and progression; Disease Progression; E2F1 protein; Esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - pathology; Esophagus; Female; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic transcription; GRB2 Adaptor Protein - genetics; GRB2 Adaptor Protein - metabolism; Grb2 protein; Health aspects; Human Genetics; Humans; Internal Medicine; Male; MAP kinase; Medicine; Medicine & Public Health; Messenger RNA; Methylation; Methyltransferase; Methyltransferases; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Mice, Knockout; Oncology; Oncology, Experimental; Post-transcription; RNA modification; RNA Stability - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Squamous cell carcinoma; Transcriptomes; Tumorigenesis; China
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-021-01978-0

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.