The transcription factor ATF2 promotes gastric cancer progression by activating the METTL3/cyclin D1 pathway.

Globally, gastric cancer (GC) is a major cause of cancer death. This study is aimed at investigating the biological functions of activating transcription factor 2 (ATF2) and the underlying mechanism in GC. In the present work, GEPIA, UALCAN, Human Protein Atlas and StarBase databases were adopted to analyze ATF2 expression characteristics in GC tissues and normal gastric tissues, and its relationships with tumor grade and patients' survival time. Quantitative real-time polymerase chain reaction (qRT-PCR) method was employed to examine ATF2 mRNA expression in normal gastric tissues, GC tissues, and GC cell lines. Cell counting kit-8 (CCK-8) and EdU assays were utilized for detecting GC cell proliferation. Cell apoptosis was detected by flow cytometry. PROMO database was applied to predict the binding site of ATF2 with the METTL3 promoter region. The binding relationship between ATF2 and the METTL3 promoter region was verified through dual-luciferase reporter gene assay and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) assay. Western blot was performed to evaluate the effect of ATF2 on METTL3 expression. METTL3-related signaling pathways were predicted using Gene Set Enrichment Analysis (GSEA) in the LinkedOmics database. It was found that, ATF2 level was elevated in GC tissues and cell lines in comparison with normal tissues and correlated with short patients' survival time. ATF2 overexpression facilitated GC cell growth and suppressed the apoptosis, whereas ATF2 knockdown suppressed GC cell proliferation and facilitated the apoptosis. ATF2 bound to the METTL3 promoter region, and ATF2 overexpression promoted the transcription of METTL3, and ATF2 knockdown restrained the transcription of METTL3. METTL3 was associated with cell cycle progression, and ATF2 overexpression enhanced cyclin D1 expression, and METTL3 knockdown reduced cyclin D1 expression. In summary, ATF2 facilitates GC cell proliferation and suppresses the apoptosis via activating the METTL3/cyclin D1 signaling pathway, and ATF2 is promising to be an anti-drug target for GC.