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Methylation-dependent regulation of HIF-1α stability restricts retinal and tumour angiogenesis

Author

Listed:
  • Yunho Kim

    (Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University)

  • Hye Jin Nam

    (Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University)

  • Junyeop Lee

    (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology
    Asan Medical Center, University of Ulsan College of Medicine)

  • Do Young Park

    (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)

  • Chan Kim

    (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology
    CHA Bundang Medical Center, CHA University)

  • Young Suk Yu

    (Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University)

  • Dongha Kim

    (Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University)

  • Se Won Park

    (Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University)

  • Jinhyuk Bhin

    (Institute for Basic Science, DGIST)

  • Daehee Hwang

    (Institute for Basic Science, DGIST)

  • Ho Lee

    (Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center)

  • Gou Young Koh

    (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)

  • Sung Hee Baek

    (Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University)

Abstract

Hypoxia-inducible factor-1α (HIF-1α) mediates hypoxic responses and regulates gene expression involved in angiogenesis, invasion and metabolism. Among the various HIF-1α posttranslational modifications, HIF-1α methylation and its physiological role have not yet been elucidated. Here we show that HIF-1α is methylated by SET7/9 methyltransferase, and that lysine-specific demethylase 1 reverses its methylation. The functional consequence of HIF-1α methylation is the modulation of HIF-1α stability primarily in the nucleus, independent of its proline hydroxylation, during long-term hypoxic and normoxic conditions. Knock-in mice bearing a methylation-defective Hif1aKA/KA allele exhibit enhanced retinal angiogenesis and tumour vascularization via HIF-1α stabilization. Importantly, S28Y and R30Q mutations of HIF-1α, found in human cancers, are involved in the altered HIF-1α stability. Together, these results demonstrate a role for HIF-1α methylation in regulating protein stability, thereby modulating biological output including retinal and tumour angiogenesis, with therapeutic implications in human cancer.

Suggested Citation

  • Yunho Kim & Hye Jin Nam & Junyeop Lee & Do Young Park & Chan Kim & Young Suk Yu & Dongha Kim & Se Won Park & Jinhyuk Bhin & Daehee Hwang & Ho Lee & Gou Young Koh & Sung Hee Baek, 2016. "Methylation-dependent regulation of HIF-1α stability restricts retinal and tumour angiogenesis," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10347
    DOI: 10.1038/ncomms10347
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