Molecular and Cellular Pathobiology Myc Posttranscriptionally Induces HIF1 Protein and Target Gene Expression in Normal and Cancer Cells

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 a subunit of HIF1 (HIF1a) under normoxic conditions and enhances HIF1a accumulation under hypoxic conditions in cells. Posttranscriptional regulation of HIF1a by Myc led to the induction of HIF1a gene targets. Normoxic HIF1a protein expression was also dependent on Myc. Functionally, HIF1a expression was required for Myc-induced anchorage-independent growth and cell proliferation. Mycdependent stabilization of HIF1a involved either disruption of binding to the VHL complex or posttranslational proteinmodifications. Taken together, our findings uncover a previously uncharacterized regulatory relationship between Myc and HIF1 that has important implications for cancer metabolism and development. Cancer Res; 72(4); 949–57. 2011 AACR.