PIASy stimulates HIF1α SUMOylation and negatively regulates HIF1α activity in response to hypoxia.
Hypoxia-inducible factor-1α (HIF1α) is a crucial regulator of the cellular response to hypoxia through its regulation of genes that control erythropoiesis, angiogenesis and anaerobic metabolism. We have previously shown that HIF1α stability is regulated by SUMOylation under the hypoxic condition. However, how HIF1α became SUMOylated during hypoxia is still unknown. In this study we identify PIASy as a specific E3 ligase for hypoxia-induced HIF1α SUMOylation. Hypoxia promotes translocation of HIF1α to the nucleus to facilitate its binding to PIASy, enabling the conjugation of HIF1α by SUMO1. We further show that PIASy negatively regulates hypoxia-induced HIF1α stability and transactivation. Knocking down PIASy increases the angiogenic activity of endothelial cells. Moreover, we show an inverse relationship between expression of PIASy and tumor angiogenesis in colon cancer. Thus, we define an important role of PIASy in hypoxia signaling through promoting HIF1α SUMOylation.
Kang
X
X
The Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, E-Institutes of Shanghai Municipal Education Commission, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Li
J
J
Zou
Y
Y
Yi
J
J
Zhang
H
H
Cao
M
M
Yeh
E T H
ET
Cheng
J
J
D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D050828:Protein Inhibitors of Activated STAT; D025842:SUMO-1 Protein; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse