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 β-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-1α. Here, we demonstrate a novel link between APC and hypoxia and show that APC and HIF-1α antagonize each other. Hypoxia results in reduced levels of APC mRNA and protein via a HIF-1α-dependent mechanism. HIF-1α represses the APC gene via a functional hypoxia-responsive element on the APC promoter. In contrast, APC-mediated repression of HIF-1α requires wild-type APC, low levels of β-catenin, and nuclear factor-κB 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.
Newton
Ian P
IP
Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.
Kenneth
Niall S
NS
Appleton
Paul L
PL
Näthke
Inke
I
Rocha
Sonia
S
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D051176:beta Catenin