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

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

SUBMITTER: Kim Y 

PROVIDER: S-EPMC4735525 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature