Microenvironment and Immunology HIF-1a Confers Aggressive Malignant Traits on Human Tumor Cells Independent of Its Canonical Transcriptional Function

Hypoxia is known to favor tumor survival and progression. Numerous studies have shown that hypoxiainducible factor 1a (HIF-1a), an oxygen-sensitive transcription factor, is overexpressed in various types of human cancers and upregulates a battery of hypoxia-responsive genes for the growth and survival of cancer cells. Although tumor progression involves the acquisition of genetic and/or epigenetic changes that confer additional malignant traits, the underlying mechanisms of these changes remain obscure. We recently identified an alternative mechanism of HIF-1a function by which HIF-1a suppresses DNA repair by counteracting c-Myc transcriptional activity that maintains gene expression. Here, we show that this HIF-a–c-Myc pathway plays an essential role in mediating hypoxic effects on malignant progression via genetic alterations, resulting in the formation of malignant tumors with aggressive local invasion and epithelial–mesenchymal transition. We show an absolute requirement of the HIF-a–c-Myc pathway for malignant progression, whereas the canonical transcription function of HIF-1a alone is insufficient and seemingly dispensable. This study indicates that HIF1a induction of genetic alteration is the underlying cause of tumor progression, especially by the hypoxic microenvironment. Cancer Res; 71(4); 1244–52. 2011 AACR.