HIF1α protein stability is increased by acetylation at lysine 709.
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.
Oregon Health & Science University Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.
Hao
H
Geng
Oregon Health & Science University Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.
Qiong
Q
Liu
Oregon Health & Science University Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.
Changhui
C
Xue
Oregon Health & Science University Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.
Larry L
LL
David
Oregon Health & Science University Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.
Tomasz M
TM
Beer
Oregon Health & Science University Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.
George V
GV
Thomas
Oregon Health & Science University Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.
Mu-Shui
MS
Dai
Oregon Health & Science University Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239. Electronic address: qianzh@ohsu.edu.
David Z
DZ
Qian
D000107:Acetylation; D019943:Amino Acid Substitution; D059447:Cell Cycle Checkpoints / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D055550:Protein Stability; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor; D000099186:Histone Deacetylase 3
D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008239:Lysine; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; D000099186:Histone Deacetylase 3; C497442:HIF1A protein, human; C110550:HDAC1 protein, human