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

Oncogene volume 29, pages 5568–5578 (2010)Cite this article

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Abstract

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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Acknowledgements

This work was supported in part by National Natural Science Foundation of China (30772462, to JC; 30800579 to XK), National Key Scientific Program in China (2009CB918403, to JC), State Key Laboratory of Oncogenes and Related Genes (91-08-06, to JC), E-Institutes of Shanghai Municipal Education Commission (E09013, to JC) and NIH grants (CA239520, to ETHY). ETHY is the McNair Scholar of the Texas Heart Institute, St Luke Episcopal Hospital.

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Authors and Affiliations

  1. 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

    X Kang, J Li, Y Zou, J Yi, M Cao & J Cheng

  2. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China

    X Kang, Y Zou & J Cheng

  3. The Department of Abdominal Surgery, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    H Zhang

  4. The Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    E T H Yeh

  5. Texas Heart Institute, St Luke’s Episcopal Hospital, Houston, TX, USA

    E T H Yeh

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  1. X Kang
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Correspondence to J Cheng.

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Kang, X., Li, J., Zou, Y. et al. PIASy stimulates HIF1α SUMOylation and negatively regulates HIF1α activity in response to hypoxia. Oncogene 29, 5568–5578 (2010). https://doi.org/10.1038/onc.2010.297

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