TY - JOUR
T1 - PPARδ interacts with the hippo coactivator YAP1 to promote SOX9 expression and gastric cancer progression
AU - Song, Shumei
AU - Wang, Zhenning
AU - Li, Yuan
AU - Ma, Lang
AU - Jin, Jiankang
AU - Scott, Ailing W.
AU - Xu, Yan
AU - Estrella, Jeannelyn Santiano
AU - Song, Yongxi
AU - Liu, Bin
AU - Johnson, Randy L.
AU - Ajani, Jaffer A.
N1 - Funding Information:
This work was supported by a Public Health Service Grant DF56338, which supports the Texas Medical Center Digestive Diseases Center (to S. Song); an MD Anderson Institutional Research Grant (3-0026317 to S. Song); grants from the Department of Defense (CA160433 to S. Song) and (CA150334 to J.A. Ajani); and NIH (CA129906, CA138671, and CA172741 to J.A. Ajani). This work was also supported by NIH/NCI under award number P30CA016672 and used the Flow Cytometry and Cellular Imaging Core Facility. We thank Drs. Sheng Ding and Min Xie from the Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, for generously providing the CA3 used in this study.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2020
Y1 - 2020
N2 - 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 patientderived 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 TEADand 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.
AB - 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 patientderived 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 TEADand 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.
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U2 - 10.1158/1541-7786.MCR-19-0895
DO - 10.1158/1541-7786.MCR-19-0895
M3 - Article
C2 - 31796534
AN - SCOPUS:85081125264
SN - 1541-7786
VL - 18
SP - 390
EP - 402
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 3
ER -