Profilin-2 promotes tumour aggressiveness in oral squamous cell carcinoma via HDAC1 modulation: implications for EMT and targeted therapy.

BACKGROUND: Profilin-2 (PFN2) is implicated in cancer metastasis, yet its significance in oral squamous cell carcinoma (OSCC) is unclear.

METHODS: We quantified PFN2 mRNA and protein in 236 OSCC tumours using qRT-PCR and immunohistochemistry, correlating findings with clinicopathology and survival. Gain- and loss-of-function studies were performed in OSCC cell lines and xenograft mice. RNA sequencing with gene-set enrichment, subcellular fractionation, and immunofluorescence delineated PFN2-dependent pathways. Sensitivity to the histone deacetylase (HDAC) inhibitor SAHA was assessed in vitro.

RESULTS: High PFN2 expression correlated with lymph-node metastasis, stage IV disease, and poorer overall and disease-free survival (p < 0.01). PFN2 increased proliferation, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and accelerated primary tumour growth plus cervical/lung metastasis in vivo; knockout produced opposite effects. Transcriptomics revealed enrichment of EMT, E2F, G2/M, and hypoxia signatures, with a 44% overlap with HDAC1 targets. PFN2 shifted HDAC1 to the cytoplasm and downregulated NuRD partners MBD3/MTA1 without altering total HDAC1. PFN2-driven EMT was independent of β-catenin nuclear entry. PFN2 overexpression sensitized cells to SAHA, enhancing G2/M arrest, apoptosis, and invasion blockade.

CONCLUSIONS: PFN2 is an oncogenic driver that promotes OSCC progression through HDAC1-dependent transcriptional reprogramming. PFN2 may serve as a prognostic biomarker and predictor of response to HDAC-targeted therapy.