PPARδ Interacts with the Hippo Coactivator YAP1 to Promote SOX9 Expression and Gastric Cancer Progression
Abstract
Despite established functions of PPARδ in lipid metabolism and tumorigenesis, the mechanisms underlying its role in gastric cancer are undefined. Here, we demonstrate that SOX9 was dramatically induced by stably expressing PPARδ and by its agonist GW501516 in human gastric cancer cell lines. PPARδ knockdown in patient-derived gastric cancer 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 gastric cancer 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 gastric cancer.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2020
- Source ID
- 10.1158/1541-7786.mcr-19-0895
Entities
People
- Ailing W. Scott
- Bin Liu
- Jaffer Ajani
- Jeannelyn Santiano Estrella
- Jiankang Jin
- Lang Ma
- Randy L Johnson
- Shumei Song
- Yan Xu
- Yongxi Song
- Yuan Li
- Zhenning Wang
Organizations
- First Affiliated Hospital, China Medical University
- National Institutes of Health
- United States Department of Defense
- United States Public Health Service
- University of Texas at Austin