Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) beta/delta and the oncogeneSrc, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPAR beta/delta activity, which directly stimulatedSrcexpression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPAR beta/delta-null mice developed fewer and smaller skin tumours, and a PPAR beta/delta antagonist prevented UV-dependentSrc stimulation. Furthermore, the expression ofPPAR beta/delta positively correlated with the expression ofSRCand EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPAR beta/delta and SRC and TGF beta 1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPAR beta/delta modulators to attenuate the development of several epithelial cancers.