METTL3-Mediated m6A mRNA Modification of FBXW7 Suppresses Lung Adenocarcinoma

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 the suppression of LUAD cells 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.

ZNF677 suppresses renal cell carcinoma progression through N6‐methyladenosine and transcriptional repression of CDKN3

“…Evidently, m 6 A RNA methylation is a major inactivation mechanism of tumour suppressor genes in tumorigenesis 27–29 . In order to investigate the roles of the m 6 A methylation modification‐associated genes in the progression of RCC, we used MeRIP‐seq to analyse the difference of the m 6 A methylation level in the five paired RCC tissues and adjacent normal tissues.…”

“…Evidently, m 6 A RNA methylation is a major inactivation mechanism of tumour suppressor genes in tumorigenesis. [27][28][29] In order to investigate the roles of the m 6 A methylation modification-associated genes in the progression of RCC, we used MeRIP-seq to analyse the difference of the m 6 A methylation level in the five paired RCC tissues and adjacent normal tissues. MeRIP-seq analysis revealed that there were 369 hypermethylated and upregulated (hyper-up) genes, 374 hypomethylated and downregulated (hypo-down) genes, 14 hypermethylated and downregulated (hyper-down) genes and two hypomethylated and upregulated (hypo-up) genes in RCC tissues compared to adjacent normal tissues (Figure 1H and Table S4).…”

The Cancer Genome Atlas Predicts the Prognosis of Lung Carcinoma Based on Genes Associated with m6A Methylation

“…METTL3 consumption signi cantly suppressed tumorigenicity and metastasis, but in patients with hepatocellular carcinoma, METTL3 was signi cantly upregulated, and the OS rate was shortened [18]. METTL3 expression was elevated in pulmonary adenocarcinoma, and METTL3 promoted the growth, survival, and invasion of human pulmonary carcinoma cells [19]. Lin et al reported that METTL3 could promote cellular growth, survival, and invasion by increasing the expression of EGFR and TAZ [20], revealing the signi cant function of METTL3 in boosting the translation of oncogenes in human pulmonary carcinoma.…”

Recent Insight on Regulations of FBXW7 and Its Role in Immunotherapy

“…A previous research conducted by our team revealed that N6methyladenosine (m 6 A) is involved in the methylated modification of FBW7 mRNA (52). M 6 A refers to the methylation of N6-adenosine in eukaryotic mRNA controlled by writers-methyltransferases, erasers-demethylases, and readers-binding proteins, which is a universal modification of mRNA and affects various pathphysiological processes including tumorgensis (53,54).…”