Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells.

ABSTRACT: c-Myc is frequently overexpressed in tumors and plays an important role in the regulation of cancer metabolism. Hypoxia-inducible factor-1 (HIF1), the master regulator of the hypoxic response, enhances tumorigenesis and influences metabolism via upregulation of the glycolytic pathway and suppression of mitochondrial respiration. Together, deregulated Myc and HIF1 cooperate to lend metabolic advantages to proliferating cancer cells and contribute to the Warburg effect. Here we show that overexpression of Myc significantly stabilizes the ? subunit of HIF1 (HIF1?) under normoxic conditions and enhances HIF1? accumulation under hypoxic conditions in cells. Posttranscriptional regulation of HIF1? by Myc led to the induction of HIF1? gene targets. Normoxic HIF1? protein expression was also dependent on Myc. Functionally, HIF1? expression was required for Myc-induced anchorage-independent growth and cell proliferation. Myc-dependent stabilization of HIF1? involved either disruption of binding to the VHL complex or posttranslational protein modifications. Taken together, our findings uncover a previously uncharacterized regulatory relationship between Myc and HIF1 that has important implications for cancer metabolism and development.

SUBMITTER: Doe MR 

PROVIDER: S-EPMC3288382 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature