Epigenetic Targeting to Overcome Radioresistance in Head and Neck Cancer

Cells with stem-like potential in head and neck squamous cell carcinoma (HNSCC) have been shown to exhibit features of intrinsic resistance to ionizing radiation. These cells, often referred to as cancer stem cells (CSCs), are characterized by an increased self-renewal and clonogenic potential, features associated with epithelial-to-mesenchymal transition (EMT), migratory behavior, and cellular plasticity. Cellular plasticity entails changes in phenotype and function in response to therapeutic pressures such as irradiation. Previously, we found that ALDH-positive CSCs are enriched in HNSCC cultures upon treatment with ionizing radiation. This process was characterized by mechanisms involving a selection of resistant populations and an induction of stem-like features. Cellular plasticity is regulated intracellularly through epigenetic mechanisms, including dynamic adaptations of DNA methylation and histone methylation, resulting in gene-specific alterations of expression levels. Therefore, we hypothesized that epigenetic targeting may prevent irradiation-induced cellular plasticity, rendering resistant HNSCC cells more sensitive. Employing a chemical library screen, we identified the histone demethylase inhibitor GSK-J1 to have a putative radiosensitizing effect that also reduces the stem-like potential of these cells.