Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10347
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Funding
- Creative Research Initiatives Program (Research Center for Chromatin Dynamics) [2009-0081563]
- Bio & Medical Technology Development Program [NRF-2013M3A9B6046565]
- Institute for Basic Science [CA1308]
- Global PhD Fellowship Program from the National Research Foundation (NRF) grant - Korean government (MSIP) [NRF-2012H1A2A1009905]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health Welfare [HI14C1976]
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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.
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