The RNA-binding protein La/SSB drives head and neck squamous cell carcinoma progression through TFAP2C-mediated transcriptional activation of FSCN1

Background: Head and neck squamous cell carcinoma (HNSCC) is marked by aggressive behavior, a paucity of effective treatment strategies, and unsatisfactory survival rates. The RNA-binding protein La/SSB is frequently overexpressed in diverse cancers, but its biological function and mechanistic contribution to HNSCC pathogenesis remain unclear. Methods: By combining transcriptome-wide RNA sequencing and chromatin accessibility analyses with functional experiments conducted both in vitro and in vivo, we sought to define the role of La/SSB in HNSCC. Patient-derived organoids (PDOs), cell-derived xenografts (CDXs), and conditional La/SSB knockout (La/ssb ^cKO ) mice were used to validate its tumorigenic and therapeutic relevance. Results: La/SSB expression was substantially elevated in HNSCC tissues and cell lines, with higher levels being associated with reduced overall survival. Functionally, La/SSB promoted tumor cell proliferation, invasion, and resistance to cisplatin. Integrative multi-omics analysis identified FSCN1 as a key downstream effector transcriptionally activated by TFAP2C. Mechanistically, La/SSB enhanced TFAP2C recruitment and chromatin accessibility at the FSCN1 promoter, thereby establishing a La/SSB–TFAP2C–FSCN1 regulatory axis that sustains oncogenic transcriptional programs. Inhibition or genetic deletion of La/SSB significantly sensitized tumors to cisplatin both in PDOs and La/ssb ^cKO mice. Conclusions: The La/SSB–TFAP2C–FSCN1 axis promotes HNSCC progression and chemoresistance by coupling RNA-binding activity with transcriptional reprogramming. Therapeutic modulation of La/SSB may offer a promising approach to improve cisplatin responsiveness in the management of HNSCC.