title: Methylation-dependent regulation of HIF-1α stability restricts retinal and tumour angiogenesis.
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 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.
authors.affiliation: Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Yunho
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Nam
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.|Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Junyeop
authors.initials: J
authors.lastname: Lee
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Park
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.|Department of Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea.
authors.forename: Chan
authors.identifier: http://orcid.org/0000-0001-9780-6155
authors.initials: C
authors.lastname: Kim
authors.affiliation: Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Yu
authors.affiliation: Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Dongha
authors.initials: D
authors.lastname: Kim
authors.affiliation: Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Se Won
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu 711-873, South Korea.
authors.forename: Jinhyuk
authors.initials: J
authors.lastname: Bhin
authors.affiliation: Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu 711-873, South Korea.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Gyeonggi-do 10408, South Korea.
authors.forename: Ho
authors.initials: H
authors.lastname: Lee
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Gou Young
authors.identifier: http://orcid.org/0000-0002-1231-1485
authors.initials: GY
authors.lastname: Koh
authors.affiliation: Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Baek
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D011496:Protein Methyltransferases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D015861:Retinal Neovascularization / Q000235:genetics* / Q000378:metabolism; D012178:Retinopathy of Prematurity / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; C562044:Setd7 protein, mouse