The RNA-binding protein La/SSB is associated with HNSCC progression and TFAP2C/FSCN1-linked transcriptional regulation.

Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive progression, frequent therapeutic resistance, and poor clinical outcomes. Although the RNA-binding protein La/SSB is aberrantly expressed in multiple malignancies, its functional and mechanistic role in HNSCC remains incompletely understood. Here, by integrating transcriptomic and chromatin accessibility profiling with comprehensive in vitro and in vivo analyses, we identify La/SSB as a putative regulator associated with HNSCC progression and cisplatin (CDDP) resistance. La/SSB was markedly upregulated in HNSCC tissues and cell lines, and elevated expression was associated with unfavorable survival. Genetic depletion of La/SSB suppressed proliferation, migration, and invasion, promoted apoptosis, and reduced tumor growth and metastatic colonization, whereas ectopic expression exerted the opposite effects. Multi-omics analyses implicated FSCN1 as a functionally relevant downstream candidate associated with La/SSB-dependent phenotypes. Mechanistically, La/SSB depletion was associated with reduced H3K27ac enrichment and diminished TFAP2C occupancy at the FSCN1 promoter, supporting a TFAP2C/FSCN1-linked regulatory framework. Importantly, loss of La/SSB significantly enhanced CDDP responsiveness in the PDO model established in this study and in vivo conditional knockout models. Clinically, elevated La/SSB showed independent prognostic value, whereas TFAP2C and FSCN1 supported a biologically associated regulatory framework linked to aggressive disease features. Collectively, our findings identify La/SSB as a clinically relevant factor associated with HNSCC progression and CDDP responsiveness, and support a TFAP2C/FSCN1-linked regulatory framework that may contribute to malignant phenotypes.