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

Title
Methylation-dependent regulation of HIF-1 alpha stability restricts retinal and tumour angiogenesis
Authors
Kim, YunhoNam, Hye JinLee, JunyeopPark, Do YoungKim, ChanYu, Young SukKim, DonghaPark, Se WonBhin, JinhyukHwang, DaeheeLee, HoKoh, Gou YoungBaek, Sung Hee
DGIST Authors
Hwang, Daehee
Issue Date
2016-01
Citation
Nature Communications, 7
Type
Article
Article Type
Article
ISSN
2041-1723
Abstract
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) mediates hypoxic responses and regulates gene expression involved in angiogenesis, invasion and metabolism. Among the various HIF-1 alpha posttranslational modifications, HIF-1 alpha methylation and its physiological role have not yet been elucidated. Here we show that HIF-1 alpha is methylated by SET7/9 methyltransferase, and that lysine-specific demethylase 1 reverses its methylation. The functional consequence of HIF-1 alpha methylation is the modulation of HIF-1 alpha stability primarily in the nucleus, independent of its proline hydroxylation, during long-term hypoxic and normoxic conditions. Knock-in mice bearing a methylation-defective Hif1a(KA/KA) allele exhibit enhanced retinal angiogenesis and tumour vascularization via HIF-1 alpha stabilization. Importantly, S28Y and R30Q mutations of HIF-1 alpha, found in human cancers, are involved in the altered HIF-1 alpha stability. Together, these results demonstrate a role for HIF-1 alpha methylation in regulating protein stability, thereby modulating biological output including retinal and tumour angiogenesis, with therapeutic implications in human cancer.
URI
http://hdl.handle.net/20.500.11750/2747
DOI
10.1038/ncomms10347
Publisher
Nature Publishing Group
Related Researcher
  • Author Hwang, Daehee Systems Biology and Medicine Lab
  • Research Interests Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
Files:
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Collection:
Department of New BiologySystems Biology and Medicine Lab1. Journal Articles


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