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

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.