METTL3-mediated m6A mRNA modification of FBXW7 suppresses lung adenocarcinoma

Yingtong Wu,Yinggang Che,Xinxin Zhang,Ning Chang,Tianyun Qiao,Jie Xiong,Yong Zhang,Jian Zhang,Ying Zhou,Leidi Xu,Jun Jiang,Bin Wu

doi:10.1186/s13046-021-01880-3

Yingtong Wu, Yinggang Che + Show 10 more

Open Access

https://doi.org/10.1186/s13046-021-01880-3

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Abstract

BackgroundFBXW7 m6A modification plays an important role in lung adenocarcinoma (LUAD) progression; however, the underlying mechanisms remain unclear.MethodsThe correlation between FBXW7 and various genes related to m6A modification was analyzed using The Cancer Genome Atlas database. The regulatory effects of METTL3 on FBXW7 mRNA m6A modification were examined in a cell model, and the underlying mechanism was determined by methylated RNA immunoprecipitation, RNA immunoprecipitation, luciferase reporter, and mutagenesis assays. In vitro experiments were performed to further explore the biological effects of METTL3-mediated FBXW7 m6A modification on LUAD development.ResultsDecreased FBXW7 expression was accompanied by downregulated METTL3 expression in human LUAD tissues and was associated with a worse prognosis for LUAD in The Cancer Genome Atlas database. m6A was highly enriched in METTL3-mediated FBXW7 transcripts, and increased m6A modification in the coding sequence region increased its translation. Functionally, METTL3 overexpression or knockdown affected the apoptosis and proliferation phenotype of LUAD cells by regulating FBXW7 m6A modification and expression. Furthermore, FBXW7 overexpression in METTL3-depleted cells partially restored LUAD cell suppression in vitro and in vivo.ConclusionsOur findings reveal that METTL3 positively regulates FBXW7 expression and confirm the tumor-suppressive role of m6A-modified FBXW7, thus providing insight into its epigenetic regulatory mechanisms in LUAD initiation and development.

Highlights

F-box and WD repeat domain-containing 7 (FBXW7) m6A modification plays an important role in lung adenocarcinoma (LUAD) progression; the underlying mechanisms remain unclear
We found that Methyltransferase-like 3 (METTL3) mediated m6A-modification of the FBXW7 mRNA coding sequence (CDS), promoting FBXW7 translation at the posttranscriptional level
The relationship between FBXW7 and METTL3 was plotted as a scatter diagram (Fig. 1e), which revealed that decreased FBXW7 protein expression was accompanied by decreased METTL3 expression and indicated a strong correlation between FBW7 and the m6A “writer.” Together, these results demonstrate that METTL3 mediates m6A modification in FBXW7 mRNA

Summary

Introduction

FBXW7 m6A modification plays an important role in lung adenocarcinoma (LUAD) progression; the underlying mechanisms remain unclear. Methods: The correlation between FBXW7 and various genes related to m6A modification was analyzed using The Cancer Genome Atlas database. The regulatory effects of METTL3 on FBXW7 mRNA m6A modification were examined in a cell model, and the underlying mechanism was determined by methylated RNA immunoprecipitation, RNA immunoprecipitation, luciferase reporter, and mutagenesis assays. In vitro experiments were performed to further explore the biological effects of METTL3-mediated FBXW7 m6A modification on LUAD development. High FBXW7 expression is independently associated with a favorable prognosis in patients with NSCLC, as it plays a negative role in NSCLC pathogenesis [4]. The m6A modifications governing FBXW7 stability and/or function in cancers and how FBXW7 expression may be modulated by m6A modification in lung cancer remain largely unknown

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