The Inhibition of Histone Lysine Demethylases Affects Head and Neck Cancer Cell Growth and Response to Cisplatin

Background/Objectives: Head and neck squamous cell carcinomas (HNSCC) are a heterogenous group of tumors, which are usually treated with surgery and radiotherapy, while chemotherapy (e.g., cisplatin), anti-EGFR, or immune checkpoint inhibitors are used to treat locoregionally advanced and recurrent cases. However, survival outcomes are still unsatisfactory, and novel augmenting treatments are required. Recently, histone lysine demethylases (KDMs) emerged as promising anti-cancer targets. In order to further characterize KDM4-6 as pharmacological targets in HNSCC, we evaluated changes in KDM4/5/6 expression in HNSCC patients, and we experimentally assessed the biological effects of inhibitors of KDM4/5/6 in HNSCC cell lines. Methods: We used online tools (TIMER, GEPIA3, UALCAN) to analyze TCGA data from HNSCC patients. Then, we used resazurin assay to assess the effect of ML324, GSK-J4, and JIB-04 (the inhibitors of KDM4, KDM6, and KDM4-6, respectively) on cell viability in two-dimensional (2D) and three-dimensional (3D) culture of FaDu, SCC-152, and Detroit-562 cells. The potential for cisplatin sensitization was also assessed. Gene/protein expression was evaluated by qPCR and antibody array. Results: We found that the majority of the analyzed KDMs were overexpressed in HNSCC, except KDM4C, KDM5D, and KDM6A. All three studied inhibitors significantly reduced cell viability in 2D and 3D cell cultures. Moreover, the pre-treatment of cells with KDM inhibitors showed moderate potential for cisplatin sensitization. In addition, the chemicals significantly reduced the expression of pluripotency markers, especially SOX2. Conclusions: In conclusion, KDM4-6 inhibitors significantly affected HNSCC cell growth, and exerted the potential for epigenetic priming in combination with cisplatin.