METTL3-mediated m6A modification of RBM39 promotes cancer stemness and tumor progression in head and neck squamous cell carcinoma

Abstract

RBM39 plays an important regulatory role in multiple cancers. However, its systematic function across pan-cancer and its specific mechanism in head and neck squamous cell carcinoma (HNSC) remain unclear. In this study, we performed pan-cancer expression and survival analyses based on TCGA and GTEx databases, combined with copy number variation and DNA methylation analyses to explore the regulatory mechanisms of RBM39. GSEA and functional enrichment were used to identify associated signaling pathways. In HNSC cells, qRT-PCR, CCK-8, Transwell, and tumor sphere formation assays were performed to validate its biological functions. In addition, RM2Target and SRAMP databases were used to investigate m 6 A-mediated regulation of RBM39, and RNA stability assays were performed for validation. The relationship between RBM39 and tumor immune infiltration as well as drug sensitivity was also evaluated. Pan-cancer analysis showed that RBM39 is aberrantly expressed in multiple cancers and is significantly associated with patient prognosis, suggesting its diagnostic value. In HNSC, RBM39 is significantly upregulated and positively correlated with tumor stage. In vitro experiments demonstrated that RBM39 knockdown significantly inhibited tumor cell proliferation and migration. Mechanistically, RBM39 activates the Wnt signaling pathway and upregulates key target genes, including CTNNB1, SOX2, OCT4, and MYC, thereby promoting cancer stem cell self-renewal. Furthermore, METTL3-mediated m 6 A modification enhances RBM39 mRNA stability and increases its expression. RBM39 acts as a key oncogenic factor in HNSC by promoting tumor progression and stemness through an m 6 A-dependent mechanism and Wnt pathway activation. It also contributes to an immunosuppressive microenvironment and drug resistance. RBM39 may serve as a potential diagnostic and therapeutic target for HNSC.