Adenomatous polyposis coli and hypoxia-inducible factor-1 alpha have an antagonistic connection

Ian P. Newton, Niall S. Kenneth, Paul L. Appleton, Inke Nathke, Sonia Rocha

    Research output: Contribution to journalArticlepeer-review

    44 Citations (Scopus)


    The tumor suppressor adenomatous polyposis coli (APC) is mutated in the majority of colorectal cancers and is best known for its role as a scaffold in a Wnt-regulated protein complex that determines the availability of beta-catenin. Another common feature of solid tumors is the presence of hypoxia as indicated by the up-regulation of hypoxia-inducible factors (HIFs) such as HIF-1 alpha. Here, we demonstrate a novel link between APC and hypoxia and show that APC and HIF-1 alpha antagonize each other. Hypoxia results in reduced levels of APC mRNA and protein via a HIF-1 alpha-dependent mechanism. HIF-1 alpha represses the APC gene via a functional hypoxia-responsive element on the APC promoter. In contrast, APC-mediated repression of HIF-1 alpha requires wild-type APC, low levels of beta-catenin, and nuclear factor-kappa B activity. These results reveal down-regulation of APC as a new mechanism that contributes to the survival advantage induced by hypoxia and also show that loss of APC mutations produces a survival advantage by mimicking hypoxic conditions.

    Original languageEnglish
    Pages (from-to)3630-3638
    Number of pages9
    JournalMolecular Biology of the Cell
    Issue number21
    Early online date15 Sept 2010
    Publication statusPublished - 1 Nov 2010


    • NF-Kappa-B
    • Beta catenin
    • Tumor suppressor
    • Cancer cells
    • Responsive element
    • Colorectal cancer
    • Gene expression regulation
    • APC
    • Autophagy
    • Pathway


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