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

DOI: http://dx.doi.org/10.1038/ncomms10347

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

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 Hif1aKA/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.

Link: http://www.nature.com/ncomms/2016/160113/ncomms10347/full/ncomms10347.html