title: Regulation of HIF-1α stability by lysine methylation.
abstract: The level and activity of critical regulatory proteins in cells are tightly controlled by several tiers of post-translational modifications. HIF-1α is maintained at low levels under normoxia conditions by the collaboration between PHD proteins and the VHL-containing E3 ubiquitin ligase complex. We recently identified a new physiologically relevant mechanism that regulates HIF-1α stability in the nucleus in response to cellular oxygen levels. This mechanism is based on the collaboration between the SET7/9 methyltransferase and the LSD1 demethylase. SET7/9 adds a methyl group to HIF-1α, which triggers degradation of the protein by the ubiquitin-proteasome system, whereas LSD1 removes the methyl group, leading to stabilization of HIF-1α under hypoxia conditions. In cells from knock-in mice with a mutation preventing HIF-1α methylation (Hif1αKA/KA), HIF-1α levels were increased in both normoxic and hypoxic conditions. Hif1αKA/KA knock-in mice displayed increased hematological parameters, such as red blood cell count and hemoglobin concentration. They also displayed pathological phenotypes; retinal and tumor-associated angiogenesis as well as tumor growth were increased in Hif1αKA/KA knock-in mice. Certain human cancer cells exhibit mutations that cause defects in HIF-1α methylation. In summary, this newly identified methylation-based regulation of HIF-1α stability constitutes another layer of regulation that is independent of previously identified mechanisms. [BMB Reports 2016; 49(5): 245-246].
authors.affiliation: School of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 08826, Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Baek
authors.affiliation: Department of Biological Sciences, Sookmyung Women's University, Seoul 04310, Korea.
authors.forename: Keun Il
authors.initials: KI
authors.lastname: Kim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008954:Models, Biological; D055550:Protein Stability
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008239:Lysine