HIF-1α confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function.

Abstract

Hypoxia is known to favor tumor survival and progression. Numerous studies have shown that hypoxia-inducible factor 1α (HIF-1α), 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-1α function by which HIF-1α suppresses DNA repair by counteracting c-Myc transcriptional activity that maintains gene expression. Here, we show that this HIF-α-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-α-c-Myc pathway for malignant progression, whereas the canonical transcription function of HIF-1α alone is insufficient and seemingly dispensable. This study indicates that HIF-1α induction of genetic alteration is the underlying cause of tumor progression, especially by the hypoxic microenvironment.