Enhancement of Cisplatin Efficacy by the Histone Demethylase Inhibitor JIB-04 in Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines

Head and neck squamous cell carcinoma (HNSCC) develops resistance to cisplatin. We investigated whether JIB-04, an inhibitor of Jumonji histone demethylases, enhances cisplatin activity in established HNSCC cell lines. Four UT-SCC cell lines originating from primary tumors and matched lymph-node metastases were treated with JIB-04 and cisplatin, alone or combined. Viability was assessed by MTT assay, and drug interactions were evaluated using the Highest Single Agent model. In UT-SCC-24A cells, we assessed BrdU incorporation, LDH release, cell-cycle distribution, and apoptosis. RNA sequencing was performed after 24 h at the same drug concentrations used in functional assays. JIB-04 reduced viability in all HNSCC lines at submicromolar concentrations, with moderate effects in BJ fibroblasts. HSA analysis identified a localized positive interaction in UT-SCC-24A, where the overall HSA score was 4.25, whereas local scores reached approximately 16–18 within a narrow low-dose range. Co-treatment further reduced DNA synthesis and increased S/G2-M accumulation and apoptosis, without significantly increasing LDH release. RNA sequencing revealed JIB-04-associated induction of integrated stress response/ATF4- and DNA damage response-related genes, alongside suppression of proliferation- and cell-cycle-associated genes. The combination retained these transcriptional features. These findings support the further investigation of JIB-04–cisplatin combinations in selected HNSCC cell-line models.