METTL3-mediated N6-methyladenosine modification of STAT5A promotes gastric cancer progression through regulating KLF4

N ⁶ -methyladenosine (m ⁶ A) modification is the predominant post-transcriptional RNA modification in eukaryotes, playing a pivotal regulatory role in various aspects of RNA fate determination, such as mRNA stability, alternative splicing, and translation. The dysregulation of critical m ⁶ A methyltransferase METTL3 is implicated in tumorigenesis and development. Here, this work shows that METTL3 is upregulated in gastric cancer tissues and associated with poor prognosis. Helicobacter pylori infection contributes to the increased expression of METTL3 in gastric cancer. Additionally, METTL3 methylates the A2318 site within the coding sequence (CDS) region of STAT5A, thereby enhancing STAT5A mRNA stability and protein expression. Furthermore, IGF2BP2 recognizes and binds METTL3-mediated m ⁶ A modification of STAT5A through its GXXG motif in KH3 and KH4 domains, leading to increased stability of STAT5A mRNA. Functional studies indicate that STAT5A overexpression remarkably enhances the proliferation and migration of GC cells, whereas STAT5A knockdown has inhibitory effects. Further nude mouse experiments show that STAT5A knockdown effectively inhibits the growth and metastasis of gastric cancer in vivo. Moreover, as a transcription factor, STAT5A represses KLF4 transcription by binding to its promoter region. The overexpression of KLF4 can counteract the oncogenic impact of STAT5A. Collectively, this study highlights the crucial role of m ⁶ A in gastric cancer and identifies potential targets for effectively controlling its progression.