Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1.
Continuous hydroxylation of the HIF-1 transcription factor alpha subunit by oxygen and 2-oxoglutarate-dependent dioxygenases promotes decay of this protein and thus prevents the transcriptional activation of many genes involved in energy metabolism, angiogenesis, cell survival, and matrix modification. Hypoxia blocks HIF-1alpha hydroxylation and thus activates HIF-1alpha-mediated gene expression. Several nonhypoxic stimuli can also activate HIF-1, although the mechanisms involved are not well known. Here we show that the glucose metabolites pyruvate and oxaloacetate inactivate HIF-1alpha decay in a manner selectively reversible by ascorbate, cysteine, histidine, and ferrous iron but not by 2-oxoglutarate or oxygen. Pyruvate and oxaloacetate bind to the 2-oxoglutarate site of HIF-1alpha prolyl hydroxylases, but their effects on HIF-1 are not mimicked by other Krebs cycle intermediates, including succinate and fumarate. We show that inactivation of HIF-1 hydroxylation by glucose-derived 2-oxoacids underlies the prominent basal HIF-1 activity commonly seen in many highly glycolytic cancer cells. Since HIF-1 itself promotes glycolytic metabolism, enhancement of HIF-1 by glucose metabolites may constitute a novel feed-forward signaling mechanism involved in malignant progression.
Lu
Huasheng
H
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
Dalgard
Clifton L
CL
Mohyeldin
Ahmed
A
McFate
Thomas
T
Tait
A Sasha
AS
Verma
Ajay
A
D001205:Ascorbic Acid / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D003545:Cysteine / Q000494:pharmacology; D017931:DNA Primers; D005978:Glutathione / Q000494:pharmacology; D006019:Glycolysis; D006639:Histidine / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062907:Oxaloacetic Acid / Q000494:pharmacology; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019289:Pyruvic Acid / Q000494:pharmacology
D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D062907:Oxaloacetic Acid; D006639:Histidine; D019289:Pyruvic Acid; D011393:Procollagen-Proline Dioxygenase; D005978:Glutathione; D003545:Cysteine; D001205:Ascorbic Acid