PPARδ Interacts with the Hippo Coactivator YAP1 to Promote SOX9 Expression and Gastric Cancer Progression

  • Shumei Song
    1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Zhenning Wang
    2Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, P.R. China.
  • Yuan Li
    1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Lang Ma
    1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Jiankang Jin
    1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Ailing W. Scott
    1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Yan Xu
    1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Jeannelyn Santiano Estrella
    3Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Yongxi Song
    2Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, P.R. China.
  • Bin Liu
    4Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Randy L. Johnson
    5Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Jaffer A. Ajani
    1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

抄録

<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Implications:</jats:title> <jats:p>Our discovery of a new model supports a distinct paradigm for PPARδ and a crucial oncogenic function of PPARδ in gastric cancer through convergence on YAP1/TEAD signaling. Therefore, PPARδ/YAP1/SOX9 axis could be a novel therapeutic target that can be translated into clinics.</jats:p> </jats:sec>

収録刊行物

  • Molecular Cancer Research

    Molecular Cancer Research 18 (3), 390-402, 2020-03-01

    American Association for Cancer Research (AACR)

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