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

Alexandra Montagner (1) , Maria B. Delgado (1) , Corinne Tallichet-Blanc (1) , Jeremy S. K. Chan (2) , Ming K. Sng (2) , Hélène Mottaz (1) , Gwendoline Degueurce (1) , Yannick Lippi (3) , Catherine Moret (1) , Michael Baruchet (1) , Maria Antsiferova (4) , Sabine Werner (4) , Daniel Hohl (5) , Talal Al Saati (6) , Pierre J. Farmer (7) , Nguan S. Tan (8, 2) , Liliane Michalik (1) , Walter Wahli (2, 1)

1 UNIL - Université de Lausanne = University of Lausanne
2 Nanyang Technological University [Singapour]
3 E23 TRiX - Transcriptomic impact of Xenobiotics
4 ETH Zürich - Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich]
5 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
6 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
7 Merck Serono
8 NUS - National University of Singapore

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.

Mots clés: Src; PPAR beta/delta; keratinocyte; Skin cancer

Mots clés: UV

Domaines: Médecine humaine et pathologie; Cancer; Toxicologie

Alexandra Montagner, Maria B. Delgado, Corinne Tallichet-Blanc, Jeremy S. K. Chan, Ming K. Sng, et al.. Src is activated by the nuclear receptor peroxisome proliferator-activated receptor beta/delta in ultraviolet radiation-induced skin cancer. EMBO Molecular Medicine, 2014, 6 (1), pp.80 - 98. ⟨10.1002/emmm.201302666⟩. ⟨hal-02631604⟩