title: 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.
authors.affiliation: Departments of Neurosurgery and Oncological Sciences, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Young-Gun
authors.initials: YG
authors.lastname: Yoo
authors.forename: Jared
authors.initials: J
authors.lastname: Christensen
authors.forename: L Eric
authors.initials: LE
authors.lastname: Huang
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D018450:Disease Progression; D016259:Genes, myc; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C497397:Arnt protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator