LSD1 demethylates HIF1α to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis

Lysine-specific demethylase 1 (LSD1), which has been considered as a potential therapeutic target in human cancer, has been known to regulate many biological functions through its non-histone substrates. Although LSD1-induced hypoxia-inducible factor alpha (HIF1 alpha) demethylation has recently been proposed, the effect of LSD1 on the relationship between HIF1 alpha post-translational modifications (PTMs) and HIF1 alpha-induced tumor angiogenesis remains to be elucidated. Here, we identify a new methylation site of the HIF1 alpha protein antagonized by LSD1 and the interplay between HIF1 alpha protein methylation and other PTMs in regulating tumor angiogenesis. LSD1 demethylates HIF1 alpha at lysine (K) 391, which protects HIF1 alpha against ubiquitin-mediated protein degradation. LSD1 also directly suppresses PHD2-induced HIF1 alpha hydroxylation, which has a mutually dependent interplay with Set9-mediated HIF1 alpha methylation. Moreover, the HIF1 alpha acetylation that occurs in a HIF1 alpha methylation-dependent manner is inhibited by the LSD1/NuRD complex. HIF1 alpha stabilized by LSD1 cooperates with CBP and MTA1 to enhance vascular endothelial growth factor (VEGF)induced tumor angiogenesis. Thus, LSD1 is a key regulator of HIF1 alpha/VEGF-mediated tumor angiogenesis by antagonizing the crosstalk between PTMs involving HIF1 alpha protein degradation.