Hypoxia-inducible factors (HIFs) are stress-responsive transcriptional regulators of cellular and physiological processes involved in
oxygen metabolism. Although much is understood about the molecular machinery that confers HIF responsiveness to
oxygen, far less is known about HIF
isoform-specific mechanisms of regulation, despite the fact that HIF-1 and HIF-2 exhibit distinct
biological roles. We recently determined that the stress-responsive genetic regulator
sirtuin 1 (
Sirt1) selectively augments HIF-2 signaling during
hypoxia. However, the mechanism by which
Sirt1 maintains activity during
hypoxia is unknown. In this report, we demonstrate that
Sirt1 gene expression increases in a HIF-dependent manner during
hypoxia in Hep3B and in HT1080 cells. Impairment of HIF signaling affects
Sirt1 deacetylase activity as decreased HIF-1 signaling results in the appearance of acetylated HIF-2α, which is detected without pharmacological inhibition of
Sirt1. We also find that
Sirt1 augments HIF-2 mediated, but not HIF-1 mediated, transcriptional activation of the isolated
Sirt1 promoter. These data in summary reveal a bidirectional link of HIF and
Sirt1 signaling during
hypoxia.