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

Nat Commun. 2016 Jan 13;7:10347. doi: 10.1038/ncomms10347.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Gene Knock-In Techniques
  • HEK293 Cells
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Hypoxia / genetics*
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Methylation
  • Mice
  • Neoplasm Transplantation
  • Neoplasms / blood supply*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Protein Methyltransferases / metabolism
  • Protein Processing, Post-Translational
  • Protein Stability
  • Retinal Neovascularization / genetics*
  • Retinal Neovascularization / metabolism
  • Retinopathy of Prematurity / genetics
  • Retinopathy of Prematurity / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • SETD7 protein, human
  • Setd7 protein, mouse