Cited 14 time in webofscience Cited 15 time in scopus

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, Y[Kim, Yunho]Nam, HJ[Nam, Hye Jin]Lee, J[Lee, Junyeop]Park, DY[Park, Do Young]Kim, C[Kim, Chan]Yu, YS[Yu, Young Suk]Kim, D[Kim, Dongha]Park, SW[Park, Se Won]Bhin, J[Bhin, Jinhyuk]Hwang, D[Hwang, Daehee]Lee, H[Lee, Ho]Koh, GY[Koh, Gou Young]Baek, SH[Baek, Sung Hee]
DGIST Authors
Bhin, J[Bhin, Jinhyuk]; Hwang, D[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, Dae Hee 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:
New BiologyETC1. Journal Articles


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