Interaction between β-catenin and HIF-1 promotes cellular adaptation to hypoxia

Aberrant activation of β-catenin promotes cell proliferation1 and initiates colorectal tumorigenesis2,3. However, the expansion of tumours and the inadequacy of their local vasculature results in areas of hypoxia where cell growth is typically constrained4,5. Here, we report a novel diversion in β-catenin signalling triggered by hypoxia. We show that hypoxia inhibits β-catenin–T-cell factor-4 (TCF-4) complex formation and transcriptional activity, resulting in a G1 arrest that involves the c-Myc–p21 axis. Additionally, we find that hypoxia inducible factor-1α (HIF-1α) competes with TCF-4 for direct binding to β-catenin. DNA–protein interaction studies reveal that β-catenin–HIF-1α interaction occurs at the promoter region of HIF-1 target genes. Furthermore, rigorous analyses indicate that β-catenin can enhance HIF-1-mediated transcription, thereby promoting cell survival and adaptation to hypoxia. These findings demonstrate a dynamic role for β-catenin in colorectal tumorigenesis, where a functional switch is instigated to meet the ever-changing needs of the tumour. This study highlights the importance of the microenvironment in transcriptional regulation.