HIF1α protein stability is increased by acetylation at lysine 709

Research output: Contribution to journalArticle

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Abstract

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
Volume287
Issue number42
DOIs
StatePublished - Oct 12 2012

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Acetylation
Protein Stability
Lysine
Proteins
Cells
Mutant Proteins
Transcriptional Activation
Neoplasms
Genes
Growth
Hypoxia

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

HIF1α protein stability is increased by acetylation at lysine 709. / Geng, Hao; Liu, Qiong; Xue, Changhui; David, Larry; Beer, Tomasz (Tom); Thomas, George; Dai, Mushui; Qian, Zheng (David).

In: Journal of Biological Chemistry, Vol. 287, No. 42, 12.10.2012, p. 35496-35505.

Research output: Contribution to journalArticle

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AU - Liu, Qiong

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AU - Thomas, George

AU - Dai, Mushui

AU - Qian, Zheng (David)

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