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

Abstract

Aberrant activation of beta-catenin promotes cell proliferation and initiates colorectal tumorigenesis. However, the expansion of tumours and the inadequacy of their local vasculature results in areas of hypoxia where cell growth is typically constrained. Here, we report a novel diversion in beta-catenin signalling triggered by hypoxia. We show that hypoxia inhibits beta-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-1alpha (HIF-1alpha) competes with TCF-4 for direct binding to beta-catenin. DNA-protein interaction studies reveal that beta-catenin-HIF-1alpha interaction occurs at the promoter region of HIF-1 target genes. Furthermore, rigorous analyses indicate that beta-catenin can enhance HIF-1-mediated transcription, thereby promoting cell survival and adaptation to hypoxia. These findings demonstrate a dynamic role for beta-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.

β - catenin is central to DUX4 -driven network rewiring in facioscapulohumeral muscular dystrophy

“…Our work implicates HIF1-a signalling as critically perturbed in FSHD and shows that HIF1A displays strong positive correlation with b-catenin in FSHD samples, providing mechanism for previous observations of involvement of downstream components of the HIF1-a pathway in FSHD [20]. HIF1-a binds b-catenin during hypoxia competitively with TCF-4 [43], which may both inhibit TCF4/b-catenindriven cell proliferation and increase transcription of hypoxic response genes, including VEGF. We found that in FSHD, correlation in gene expression between b-catenin, and both HIF1A and TCF-4, significantly increases, resulting in elevated angiogenic genes such as VEGF, providing an explanation for the hallmark oxidative stress sensitivity in FSHD, as well as retinal vasculature abnormalities [4,5].…”

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

“…Perhaps HIF is regulated by oncogenes in addition to acting through the pathway regulated by hypoxia. For example, interactions of HIF1 with b-catenin in colon cancer cell lines have been reported (Kaidi et al, 2007). Also, it is possible that as both mature and immature vessels are being assessed, this may reflect effects of other growth factors and vascular differentiation.…”

The role of oxygen availability in embryonic development and stem cell function

“…Hypoxia downregulates β-catenin (via its interaction with HIF-1α), which is stabilized in response to Wnt signalling and forms an active transcriptional complex with lymphoid enhancer factor/T-cell factor-4 (LEF/TCF4). Kaidi and colleagues demonstrated that HIF-1α competes with TCF4 for direct binding to β-catenin, resulting in hypoxia-mediated cell-cycle arrest and inhibition of transcriptional activity 74 . Intriguingly, β-catenin can also promote HIF-1α-mediated transcriptional activity, which might help cells to adapt to severe hypoxia 74.…”