Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha.
To survive in hypoxic environments, organisms must be able to cope with redox imbalance and oxygen deficiency. The SIRT1 deacetylase and the HIF-1alpha transcription factor act as redox and oxygen sensors, respectively. Here, we found that SIRT1 binds to HIF-1alpha and deacetylates it at Lys674, which is acetylated by PCAF. By doing so, SIRT1 inactivated HIF-1alpha by blocking p300 recruitment and consequently repressed HIF-1 target genes. During hypoxia, SIRT1 was downregulated due to decreased NAD(+) levels, which allowed the acetylation and activation of HIF-1alpha. Conversely, when the redox change was attenuated by blocking glycolysis, SIRT1 was upregulated, leading to the deacetylation and inactivation of HIF-1alpha even in hypoxia. In addition, we confirmed the SIRT1-HIF-1alpha interaction in hypoxic mouse tissues and observed in vivo that SIRT1 has negative effects on tumor growth and angiogenesis. Our results suggest that crosstalk between oxygen- and redox-responsive signal transducers occurs through the SIRT1-HIF-1alpha interaction.
Lim
Ji-Hong
JH
Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
Lee
Yoon-Mi
YM
Chun
Yang-Sook
YS
Chen
Junjie
J
Kim
Ja-Eun
JE
Park
Jong-Wan
JW
D000107:Acetylation; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010084:Oxidation-Reduction; D021381:Protein Transport; D056564:Sirtuin 1 / Q000378:metabolism*; D014183:Transplantation, Heterologous; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050880:p300-CBP Transcription Factors; D056564:Sirtuin 1