UV-induced senescence in the epidermis and its impact on skin cancer development

Epidermal skin tumors are among the most common human cancers, and are caused mainly by exposure to ultraviolet radiation (UVR) from sunlight. This radiation provokes DNA damage that can generate cancer-driving mutations. Cellular senescence is a central damage response program, which blocks tumorigenesis by cell-cycle arrest. However, we recently showed that induction of p16Ink4a-expressing senescent keratinocytes in the epidermis stimulated neighbouring cells to hyperproliferate, and promoted tumorigenesis. Here we study whether UVR induces senescence in epidermal keratinocytes and whether senescence influences the development of epithelial skin cancer. We exposed cultured keratinocytes and mouse skins to different doses and regimens of ultraviolet B (UVB) light and examined the induction of senescence. We found that a single dose of low level UVB-irradiation induces senescence in murine keratinocytes, whereas higher doses induce cell death. Exposure of mice to low-level, chronic UVB irradiation led to activation of senescence markers in the epidermis and to hyperplasia. We are further characterizing the traits of UVB-induced senescent cells, and the potential for treatment with senolytic drugs, which eliminate senescent cells, on UVB-induced hyperplasia. We suggest that senescence plays a role in early skin cancers and that senolytic drugs may be considered as a potential treatment.