METTL3 stabilizes DDX17 mRNA via IGF2BP2-mediated m6A modification to suppress endometrial cancer progression.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.