METTL3-mediated m6A mRNA modification of FBXW7 suppresses lung adenocarcinoma

Journal of Experimental & Clinical Cancer Research

Xinxin Zhang¹  Leidi Xu¹  Bin Wu¹  Yinggang Che¹  Yingtong Wu¹  Jun Jiang¹  Yong Zhang¹  Ying Zhou¹  Jie Xiong¹  Jian Zhang¹  Tianyun Qiao²  Ning Chang³ 

[1] Department of Respiratory Diseases, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, 710032, Xi’an, People’s Republic of China;Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Baqiao District, 710038, Xi’an, Shaanxi, People’s Republic of China;State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Chang-Le Xi Street #169, 710032, Xi’an, People’s Republic of China;

关键词: METTL3;    FBXW7;    Lung adenocarcinoma;    mA;    Epigenetic modification;   

DOI  :  10.1186/s13046-021-01880-3

来源: Springer

【 摘 要 】

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.

【 授权许可】

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