PIASy stimulates HIF1α SUMOylation and negatively regulates HIF1α activity in response to hypoxia

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.
Oncogene (Impact Factor: 8.46). 10/2010; 29(41):5568-78. DOI: 10.1038/onc.2010.297
Source: PubMed


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.

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Available from: Edward T H Yeh, Sep 22, 2014
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    • "For an example, mutational loss of the von Hippel–Lindau protein's ability to bind HIF-1α as part of the ubiquitin ligase complex that marks HIF-1α for proteasomal degradation increases HIF-1α protein levels and promotes renal tumorigenesis 60,61. Another emerging mechanism is posttranslational modification of HIF-1α by small ubiquitin-related modifier (SUMO) under hypoxia to initiate ubiquitin-mediated proteasomal degradation of HIF-1α 62,63. SUMOylation is regulated by activating enzymes (E1), conjugating enzymes (E2), and ligating enzymes (E3 ligases) and reversed by SUMO-specific isopeptidases (sentrin/SUMO-specific proteases [SENPs]) 64. "
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    • "An earlier study of colon cancer demonstrated high PIAS4 expression with little angiogensis in colon cancer tissue, which was associated with enhanced HIF1α sumoylation and deactivation of HIF1α activity (Kang et al, 2010). By contrast, our study showed that induction of PIAS4 is positively correlated with induction of HIF1α. "
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    • "PIASy has been identified as the E3 ligase for hypoxia-induced HIF-1α SUMOylation. As a result, PIASy negatively regulates HIF-1α stability and activity [110]. However, different SUMOylation inducers may have distinct efficiencies, as HIF-1α has also been reported to be stabilized with increased SUMOylation by RSUME, an enhancer of SUMO conjugation, during hypoxia [111]. "
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