METTL3 stabilizes DDX17 mRNA via IGF2BP2-mediated m6A modification to suppress endometrial cancer progression
Endometrial cancer (EC), a type of uterine cancer, is witnessing a global increase in incidence. Despite advancement in diagnosis and treatment, metastatic or recurrent EC often exhibits a poor prognosis, necessitating novel therapeutic strategies. DEAD-box helicase 17 (DDX17) is implicated in several cancers. Our study aimed to uncover the biological function and molecular mechanism of DDX17 in EC. EC and matched adjacent normal tissues from 80 patients were analyzed; DDX17 mRNA/protein expression was quantified via RT-qPCR and immunoblotting in clinical specimens and cell lines (HEC-1A, HEC-1B, Ishikawa), with functional assays (proliferation/migration/invasion) performed following DDX17 overexpression in vitro, while xenograft modeling in BALB/c nude mice enabled in vivo validation through immunofluorescence and immunohistochemical staining; mechanistic studies employed RNA immunoprecipitation (RIP-PCR), m6A-specific RNA immunoprecipitation (MeRIP-PCR), and protein interaction analyses. DDX17 was significantly downregulated in EC tissues/cells, correlating with poor prognosis in clinical cohorts. Overexpression of DDX17 suppressed tumorigenesis both in vitro and in vivo through PI3K/AKT pathway inactivation. METTL3-mediated m6A modification stabilized DDX17 mRNA, with IGF2BP2 specifically recognizing m6A-modified transcripts. Critically, METTL3 ablation reversed DDX17 stabilization and abolished its tumor-suppressive effects, while PI3K inhibition (LY294002) phenocopied METTL3 restoration in rescuing DDX17 deficiency-induced oncogenicity. METTL3-mediated m6A modification stabilizes DDX17 to suppress EC cell proliferation, migration, and invasion through an IGF2BP2-dependent mechanism by inactivating the PI3K/AKT pathway.