Fig. 1. Schematic model of regulation of HIF-1α protein stability. Under normoxic conditions, HIF-1α protein stability is regulated by PHD-dependent hydroxylation in the cytoplasm. Hydroxylated HIF-1α is degraded by 26S proteasomes to maintain low HIF-1α protein levels. In contrast, SET7/9-dependent methylation and LSD1-dependent demethylation of HIF-1α regulate protein stability primarily in the nucleus in a hydroxylation-independent manner during normoxia. Upon hypoxia, HIF-1α is stabilized by LSD1-dependent demethylation in the nucleus.