Suppression of hypoxia-inducible factor 1α (HIF-1α) transcriptional activity by the HIF prolyl hydroxylase EGLN1

Abstract

The cellular response to hypoxia is, at least in part, mediated by the transcriptional regulation of hypoxia-responsive genes involved in balancing the intracellular ATP production and consumption. Recent evidence suggests that the transcription factor, HIF-1α, functions as a master regulator of oxygen homeostasis by controlling a broad range of cellular events in hypoxia. In normoxia, HIF-1α is targeted for destruction via prolyl hydroxylation, an oxygen-dependent modification that signals for recognition by the ubiquitin ligase complex containing the von Hippel-Lindau tumor suppressor. Three HIF prolyl hydroxylases (EGLN1, EGLN2, and EGLN3) have been identified in mammals, among which EGLN1 and EGLN3 are hypoxia-inducible at their mRNA levels in an HIF-1α-dependent manner. In this study, we demonstrated that apart from promoting HIF-1α proteolysis in normoxia, EGLN1 specifically represses HIF-1α transcriptional activity in hypoxia. Ectopic expression of EGLN1 inhibited HIF-1α transcriptional activity without altering its protein levels in a von Hippel-Lindau-deficient cell line, indicating a discrete activity of EGLN1 in transcriptional repression. Conversely, silencing of EGLN1 expression augmented HIF-1α transcriptional activity and its target gene expression in hypoxia. Thus, we proposed that the accumulated EGLN1 in hypoxia acts as a negative-feedback mechanism to modulate HIF-1α target gene expression. Our finding also provided new insight into the pharmacological manipulation of the HIF prolyl hydroxylase for ischemic diseases.