Transcriptional and UV-response regulatory role of PPARb in Normal Human Keratinocytes

ABSTRACT: Solar radiation is the major source of human exposure to UV radiation, the major carcinogen in skin cancers, by triggering a number of cellular responses that can indirectly or directly induce DNA damage. Skin cells attempt to repair these damages by activating cascades of DNA Damage Response mechanisms to safeguard genome integrity, thereby preventing skin cancers. The role of PPARb - a druggable transcription factor, in the development of UV-dependent skin cancers is not mechanistically elucidated. We have shown previously that PPARb knockout mice are less prone to UV-induced skin cancers. Here, we report on our global transcriptomic analysis revealing that PPARb directly regulates gene expression programs associated with cell cycle and DNA repair pathways in normal human epidermal keratinocytes. We show that in these cells, as well as in malignant human keratinocytes and in human melanoma cells, PPARb controls cellular proliferation and cell cycle progression and its depletion leads to cell cycle arrest. We also show that PPARb controls the response of normal human epidermal keratinocytes to UV-induced DNA damage. PPARb depletion decreases the expression and/or activation of multiple effectors of DNA Damage Response (DDR) pathway and favours the apoptotic response of human keratinocytes to UV irradiation. Our preclinical data of a PDX melanoma model demonstrated that the depletion or inhibition of PPARb delays of blocks tumor formation. Our data suggest that PPARb inhibition can be considered as a therapeutic target for the prevention of UV-induced skin cancers in vulnerable population, by attenuating the DDR and eliminating skin cells with high UV-induced mutational burden.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263846 | GEO | 2024/12/18

REPOSITORIES: GEO