HIF1α protein stability is increased by acetylation at lysine 709

Hao Geng, Qiong Liu, Changhui Xue, Larry L. David, Tomasz M. Beer, George V. Thomas, Mu Shui Dai, David Z. Qian

Research output: Contribution to journalArticlepeer-review

102 Scopus citations


Lysine acetylation regulates protein stability and function. p300 is a component of the HIF-1 transcriptional complex and positively regulates the transactivation of HIF-1. Here, we show a novel molecular mechanism by which p300 facilitates HIF-1 activity. p300 increases HIF-1α (HIF1α) protein acetylation and stability. The regulation can be opposed by HDAC1, but not by HDAC3, and is abrogated by disrupting HIF1α-p300 interaction. Mechanistically, p300 specifically acetylates HIF1α at Lys-709, which increases the protein stability and decreases polyubiquitination in both normoxia and hypoxia. Compared with the wild-type protein, a HIF1α K709A mutant protein is more stable, less polyubiquitinated, and less dependent on p300. Overexpression of the HIF1α wild-type or K709A mutant in cancer cells lacking the endogenous HIF1α shows that the K709A mutant is transcriptionally more active toward the HIF-1 reporter and some endogenous target genes. Cancer cells containing the K709A mutant are less sensitive to hypoxia-induced growth arrest than the cells containing the HIF1α wild-type. Taken together, these data demonstrate a novel biological consequence upon HIF1α-p300 interaction, in which HIF1α can be stabilized by p300 via Lys-709 acetylation.

Original languageEnglish (US)
Pages (from-to)35496-35505
Number of pages10
JournalJournal of Biological Chemistry
Issue number42
StatePublished - Oct 12 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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