Background: FBXW7 mA modification plays an important role in lung adenocarcinoma (LUAD) progression; however, the underlying mechanisms remain unclear.
Methods: The correlation between FBXW7 and various genes related to mA modification was analyzed using The Cancer Genome Atlas database. The regulatory effects of METTL3 on FBXW7 mRNA mA 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 mA modification on LUAD development.
Results: Decreased 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. mA was highly enriched in METTL3-mediated FBXW7 transcripts, and increased mA 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 mA modification and expression. Furthermore, FBXW7 overexpression in METTL3-depleted cells partially restored LUAD cell suppression in vitro and in vivo.
Conclusions: Our findings reveal that METTL3 positively regulates FBXW7 expression and confirm the tumor-suppressive role of mA-modified FBXW7, thus providing insight into its epigenetic regulatory mechanisms in LUAD initiation and development.
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| http://dx.doi.org/10.1186/s13046-021-01880-3 | DOI Listing |
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