HOXA1 promotes radioresistance via activation of the ERK/HIF1A signaling pathway

Oral squamous cell carcinoma (OSCC), the most common subtype of head and neck squamous cell carcinoma (HNSCC), remains a major clinical challenge due to treatment resistance, particularly radioresistance. Despite advances in surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy, the 5-year survival rate for HNSCC patients has improved only marginally. HOXA1, a member of the homeobox (HOX) gene family, has been implicated in tumor progression and prognosis across several cancer types. However, its specific role in OSCC and its potential involvement in radioresistance remain unclear. In this study, we analyzed HOXA1 expression in OSCC patient samples with diverse clinicopathological features and generated HOXA1-deficient OSCC cell lines using CRISPR/Cas9 technology. Following validation of stable knockout, we assessed the expression of genes associated with proliferation, migration, and invasion at both mRNA and protein levels. HOXA1-deficient cells exhibited markedly decreased colony formation and cell viability after irradiation compared with control cells, indicating that HOXA1 contributes to radioresistance. Transcriptomic enrichment analysis further revealed an upregulation of focal adhesion-related genes in HOXA1-deficient OSCC cells. Mechanistically, HOXA1 was found to activate a focal adhesion via the ERK/HIF1A signaling pathway, underscoring its pivotal role in OSCC progression and therapeutic response.