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.
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We would like to thank: P. Ratcliffe and C. Pugh for providing HIF-1α expression constructs, B. Vogelstein for providing β-catenin expression vectors, K. Basler and C. Mosimann for the β-catenin truncations, E. Fearon for the TCF-4DN expression vector, K. Malik for technical advice, K. Brown and B. Hassan for the critical reading of the manuscript. This work was funded by a scholarship from the Algerian Government, the Citrina foundation, and a programme grant from Cancer Research UK.
The authors declare no competing financial interests.
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Kaidi, A., Williams, A. & Paraskeva, C. Interaction between β-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol 9, 210–217 (2007). https://doi.org/10.1038/ncb1534
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