Methylation dependent regulation of HIF 1a stability restricts retinal and tumour angiogenesis
Hypoxia inducible factor 1a (HIF 1a) mediates hypoxic responses and regulates gene expression involved in angiogenesis, invasion and metabolism. Among the various HIF 1a posttranslational modifications, HIF 1a methylation and its physiological role have not yet been elucidated. Here we show that HIF 1a is methylated by SET7/9 methyltransferase, and that lysine specific demethylase 1 reverses its methylation. The functional consequence of HIF 1a methylation is the modulation of HIF 1a 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 1a stabilization. Importantly, S28Y and R30Q mutations of HIF 1a, found in human cancers, are involved in the altered HIF 1a stability. Together, these results demonstrate a role for HIF 1a methylation in regulating protein stability, thereby modulating biological output including retinal and tumour angiogenesis, with therapeutic implications in human cancer.
Nature communications