METTL3-mediated m⁶A mRNA modification of FBXW7 suppresses lung adenocarcinoma.

ABSTRACT:

Background

FBXW7 m⁶A 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 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.

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. 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.

Conclusions

Our 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.

SUBMITTER: Wu Y 

PROVIDER: S-EPMC7936500 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature