The inhibitors of KDM4 and KDM6 histone lysine demethylases enhance the anti-growth effects of erlotinib and HS-173 in head and neck cancer cells.

Novel therapeutics are required to improve treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients. Histone lysine demethylases (KDM) have emerged recently as new potential drug targets for HNSCC therapy. They might also potentiate the action of the inhibitors of EGFR and PI3K signaling pathways. This study aimed at evaluating the anti-cancer effects of KDM4 (ML324) and KDM6 (GSK-J4) inhibitors and their combinations with EGFR (erlotinib) and PI3K (HS-173) inhibitors in HNSCC cells. The effect of the inhibitors on the viability of CAL27 and FaDu cells was evaluated using resazurin assay. The effect of the chemicals on cell cycle and apoptosis was assessed using propidium iodide and Annexin V staining, respectively. The effect of the compounds on gene expression was determined using qPCR and Western blot. The changes in cell cycle distribution upon treatment with the compounds were small to moderate, with the exception of erlotinib, which induced G1 arrest. However, all the compounds and their combinations induced apoptosis in both cell lines. These effects were associated with changes in the level of expression of CDKN1A, CCND1 and BIRC5. The inhibition of KDM4 and KDM6 using ML324 and GSK-J4, respectively, can be regarded as a novel therapeutic strategy in HNSCC.