PPARdelta Interacts with the Hippo Coactivator YAP1 to Promote SOX9 Expression and Gastric Cancer Progression
Menée sur des lignées cellulaires de cancer humain de l'estomac et à l'aide d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel le récepteur PPAR delta, en interagissant avec le co-activateur YAP1 de la voie de signalisation Hippo, favorise l'expression du facteur de transcription SOX9 et la progression tumorale
Despite established functions of PPARδ in lipid metabolism and tumorigenesis, the mechanisms underlying its role in gastric cancer (GC) are undefined. Here, we demonstrate that SOX9 was dramatically induced by stably expressing PPARδ and by its agonist GW501516 in human GC cell lines. PPARδ knockdown in patient-derived GC cells dramatically reduced SOX9 expression and transcriptional activity, with corresponding decreases in invasion and tumor sphere formation. Mechanistically, PPARδ induced SOX9 transcription through direct interaction with and activation of the Hippo coactivator YAP1. PPARδ-YAP1 interaction occurred via the C-terminal domain of YAP1, and both TEAD and PPARE binding sites were required for SOX9 induction. Notably, CRISPR/Cas9-mediated genetic ablation of YAP1 or SOX9 abolished PPARδ-mediated oncogenic functions. Finally, expression of PPARδ, YAP1 and SOX9 were significantly correlated with each other and with poor survival in a large cohort of human GC tissues. Thus, these findings elucidate a novel mechanism by which PPARδ promotes gastric tumorigenesis through interaction with YAP1 and highlights the PPARδ/YAP1/SOX9 axis as a novel therapeutic target in human GC. Implications: Our discovery of a new model supports a distinct paradigm for PPARδ and a crucial oncogenic function of PPARδ in GC through convergence on YAP1/TEAD signaling. Therefore, PPARδ/YAP1/SOX9 axis could be a novel therapeutic target that can be translated into clinics.