Journal Article

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

Yu, Young Suk, Lee, Junyeop, Baek, Sung Hee, Bhin, Jinhyuk, Hwang, Daehee, Park, Do Young, Park, Se Won, Koh, Gou Young, Lee, Ho, Kim, Chan, Kim, Yunho, Kim, Dongha, Nam, Hye Jin

2016

Overview

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. HIF-1α is a pivotal protein involved in angiogenesis and is known to be regulated posttranslationally. Here, the authors show that HIF-1α is methylated by Set7/9 methyltransferase, which reduces protein stability and contributes to reduced angiogenesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 38 / 38/77 / 631/337/458/1648 / 631/67/2328 / Animals / Cell Line, Tumor / Disease Models, Animal / Gene Knock-In Techniques / HEK293 Cells / HeLa Cells / Histone-Lysine N-Methyltransferase - metabolism / Humanities and Social Sciences / Humans / Hypoxia - genetics / Hypoxia - metabolism / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Methylation / Mice / multidisciplinary / 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 / Science / Science (multidisciplinary)