NSUN2-mediated RNA 5-methylcytosine promotes esophageal squamous cell carcinoma progression via LIN28B-dependent GRB2 mRNA stabilization
Open Access
- 3 August 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (39), 5814-5828
- https://doi.org/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.Keywords
This publication has 57 references indexed in Scilit:
- NSun2-Mediated Cytosine-5 Methylation of Vault Noncoding RNA Determines Its Processing into Regulatory Small RNAsCell Reports, 2013
- Identification of direct targets and modified bases of RNA cytosine methyltransferasesNature Biotechnology, 2013
- Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal-Recessive Intellectual DisabilityAmerican Journal of Human Genetics, 2012
- High expression of Lin28 is associated with tumour aggressiveness and poor prognosis of patients in oesophagus cancerBritish Journal of Cancer, 2012
- Widespread occurrence of 5-methylcytosine in human coding and non-coding RNANucleic Acids Research, 2012
- Genomic gain of 5p15 leads to over-expression of Misu (NSUN2) in breast cancerCancer Letters, 2010
- 5-methylcytosine in RNA: detection, enzymatic formation and biological functionsNucleic Acids Research, 2009
- Lin28 promotes transformation and is associated with advanced human malignanciesNature Genetics, 2009
- Inhibition of Tumor Metastasis by a Growth Factor Receptor Bound Protein 2 Src Homology 2 Domain–Binding AntagonistCancer Research, 2007
- The phosphatidylinositol 3-Kinase–AKT pathway in human cancerNature Reviews Cancer, 2002