Response of head and neck epithelial cells to a DNA damage‐differentiation checkpoint involving polyploidization

Background Squamous epithelia of the head and neck undergo continuous cell renewal and are continuously exposed to mutagenic hazard, the main cause of cancer. How they maintain homeostasis upon cell cycle deregulation is unclear. Methods To elucidate how head and neck epithelia respond to cell cycle stress, we studied human keratinocytes from various locations (oral mucosa, tonsil, pharynx, larynx, and trachea). We made use of genotoxic or mitotic drugs (doxorubicin [DOXO], paclitaxel, and nocodazole), or chemical inhibitors of the mitotic checkpoint kinases, Aurora B and polo‐like‐1. We further tested the response to inactivation of p53, ectopic cyclin E, or to the chemical carcinogen 7,12‐dimethylbenz[a]anthracene (DMBA). Results All treatments provoked DNA damage or mitosis impairment and strikingly triggered squamous differentiation and polyploidization, resulting in irreversible loss of clonogenic capacity. Conclusion Keratinocytes from head and neck epithelia share a cell‐autonomous squamous DNA damage‐differentiation response that is common to the epidermis and might continuously protect them from cancer.