| First Author | Kim Y | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 10347 | PubMed ID | 26757928 |
| Mgi Jnum | J:235887 | Mgi Id | MGI:5803912 |
| Doi | 10.1038/ncomms10347 | Citation | Kim Y, et al. (2016) Methylation-dependent regulation of HIF-1alpha stability restricts retinal and tumour angiogenesis. Nat Commun 7:10347 |
| abstractText | Hypoxia-inducible factor-1alpha (HIF-1alpha) mediates hypoxic responses and regulates gene expression involved in angiogenesis, invasion and metabolism. Among the various HIF-1alpha posttranslational modifications, HIF-1alpha methylation and its physiological role have not yet been elucidated. Here we show that HIF-1alpha is methylated by SET7/9 methyltransferase, and that lysine-specific demethylase 1 reverses its methylation. The functional consequence of HIF-1alpha methylation is the modulation of HIF-1alpha 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-1alpha stabilization. Importantly, S28Y and R30Q mutations of HIF-1alpha, found in human cancers, are involved in the altered HIF-1alpha stability. Together, these results demonstrate a role for HIF-1alpha methylation in regulating protein stability, thereby modulating biological output including retinal and tumour angiogenesis, with therapeutic implications in human cancer. |
