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

Jiachun Su,Junzhong Lin,Xudong Huang,Ying Ye,Shaoping Zhang,Guandi Wu,Mei Li,Rui Li,Zexian Liu,Zhixiang Zuo,Lingxing Zeng,Shuang Deng,Junge Deng,Ling Pan,Ruihong Bai,Lisha Zhuang,Jialiang Zhang,Yanfen Zheng,Dong Lin ,Jian Zheng

doi:10.1038/s41388-021-01978-0

Abstract

5-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.

Highlights

Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers with only ~19% of 5-year survival [1, 2]
Aberrant upregulation of NSUN2 plays an oncogenic role in ESCC To determine the role of mRNA m5C modification in ESCC, we evaluated the expression levels of two major mRNA m5C
NSUN2 expression is positively regulated by E2F Transcription Factor 1 (E2F1) To explore why NSUN2 is overexpressed in ESCC, we looked at genomic alterations including CNV and methylation status of NSUN2 in ESCC tissues derived from different datasets but the results were negative (Supplementary Fig. 2A, B)

Summary

Introduction

Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers with only ~19% of 5-year survival [1, 2]. ESCC patients eventually die of cancer progression due to lack of effective treatment modalities [3]. Recent discoveries have demonstrated that aberrations in epigenetic regulation, such as RNA methylation, are crucial hallmarks of tumor initiation, progression, and recurrence [4]. Accumulating evidence confirms that m5C modification regulates multiple RNA metabolic and biological processes, such as RNA stability [12, 13], RNA export [9], RNA translation [14, 15], and RNA processing [16, 17]. NSUN2 and NSUN6 are two major methyltransferase catalyzing m5C modification of mammalian mRNAs [7, 9, 11, 18]

Methods

Results

Conclusion