β-Catenin and Peroxisome Proliferator-activated Receptor-δ Coordinate Dynamic Chromatin Loops for the Transcription of Vascular Endothelial Growth Factor A Gene in Colon Cancer Cells

Vascular endothelial growth factor A (VEGFA) mRNA is regulated by beta-catenin and peroxisome proliferator activated receptor delta (PPAR-delta) activation in colon cancer cells, but the detailed mechanism remains to be elucidated. As chromatin loops are generally hubs for transcription factors, we tested here whether beta-catenin could modulate chromatin looping near the VEGFA gene and play any important role for PPAR-delta activated VEGFA transcription. First, we identified the far upstream site as an important site for VEGFA transcription by luciferase assay and chromatin immunoprecipitation in colorectal carcinoma HCT116 cells. Chromatin conformation capture analysis also revealed the chromatin loops formed by the beta-catenin bindings on these sites near the VEGFA gene. Dynamic association and dissociation of beta-catenin/TCF-4/PPAR-delta on the far upstream site and beta-catenin/NF-kappa B p65 on the downstream site were also detected depending on PPAR-delta activation. Interestingly, beta-catenin-mediated chromatin loops were relieved by PPAR-delta activation, suggesting a regulatory role of beta-catenin for VEGFA transcription. Based on these data, we propose a model for PPAR-delta-activated VEGFA transcription that relies on beta-catenin-mediated chromatin looping as a prerequisite for the activation. Our findings could extend to other beta-catenin regulated target genes and could provide a general mechanism and novel paradigm for beta-catenin-mediated oncogenesis.