The m6A reader YTHDF1 facilitates nasopharyngeal carcinoma proliferation and migration via c-MYC

N6-methyladenosine (m6A), the most prevalent mRNA modification in eukaryotes, is critical for posttranscriptional regulation. The m6A reader YTH domain-containing family protein 1 (YTHDF1) acts as an oncogene in multiple malignancies, yet its specific roles and regulatory mechanisms in nasopharyngeal carcinoma (NPC) have not been fully elucidated. This study elucidates a novel epitranscriptional axis whereby YTHDF1 drives NPC progression via posttranscriptional regulation of c-MYC. Clinical analyses reveal YTHDF1 is overexpressed in a subset of NPC specimens, with high expression correlating with advanced stage and poor patient outcomes, supporting its potential as a prognostic biomarker. Functional assays demonstrate that YTHDF1 enhances NPC proliferation, migration, and invasion in vitro, while promoting tumor growth and metastasis in vivo. Mechanistically, m6A RNA immunoprecipitation sequencing identifies a conserved m6A modification peak within the 3' untranslated region near the stop codon of c-MYC mRNA, distinct from those reported in other malignancies, that is specifically recognized by YTHDF1, as validated by RIP-qPCR. Unlike its role in other cancers, where YTHDF1 primarily stabilizes c-MYC mRNA, in NPC it exerts dual posttranscriptional control: prolonging c-MYC mRNA half-life to enhance stability and increasing translational efficiency (confirmed by ribosome profiling) to elevate c-MYC protein levels, forming a coordinated regulatory network. Luciferase reporter assays confirm the functional necessity of this m6A site, as mutations abrogate YTHDF1-mediated regulation. Importantly, the m6A inhibitor STM2457 reverses YTHDF1-driven oncogenic phenotypes. These findings uncover a novel mechanism by which YTHDF1 regulates c-MYC through combined effects on mRNA stability and translation, advancing understanding of m6A-mediated oncogenesis and offering new insights into epitranscriptional control of cancer progression.