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Supplementary Figure legends 1-7 from PPARδ Interacts with the Hippo Coactivator YAP1 to Promote SOX9 Expression and Gastric Cancer Progression

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posted on 2023-04-03, 17:06 authored by Shumei Song, Zhenning Wang, Yuan Li, Lang Ma, Jiankang Jin, Ailing W. Scott, Yan Xu, Jeannelyn Santiano Estrella, Yongxi Song, Bin Liu, Randy L. Johnson, Jaffer A. Ajani

Supplemental Figure 1. PPARÎ'ï�¤and its agonist activate SOX9 transcription, while its antagonist suppresses SOX9 transcription and expression. Supplemental Figure 2. Diagram demonstrates cloning of human YAP1 and PPARÎ'ï�¤and their major domains as depicted. Supplemental Figure 3. Sequential ChIP using YAP1 and PPARÎ'ï�¤ antibodies in PPARÎ' transfected GAC (AGS) cells. Supplemental Figure 4. Mutation of the TEAD binding site of SOX9 promoter diminished the SOX9 transcriptional activity induced by PPARÎ'ï�¤agonist GW501516. Supplemental Figure 5. PPARÎ' and its agonist GW501516 activation of YAP1 expression and increased the binding of PPARÎ' and YAP1.Supplemental Figure 6. PPARÎ'Interacts with YAP1 by Yeast two-hybrid analyses. Supplemental Figure 7. PPARÎ' promotes oncogenic functions of GAC cells in vitro and in vivo.

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ARTICLE 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. 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.

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