title: Differential roles of Sirt1 in HIF-1α and HIF-2α mediated hypoxic responses.
abstract: Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) determine cancer cell fate under hypoxia. Despite the similarities of their structures, HIF-1α and HIF-2α have distinct roles in cancer growth under hypoxia, that is, HIF-1α induces growth arrest whereas HIF-2α promotes cell growth. Recently, sirtuin 1 (Sirt1) was reported to fine-tune cellular responses to hypoxia by deacetylating HIF-1α and HIF-2α. Yet, the roles of Sirt1 in HIF-1α and HIF-2α functions have been controversial. We here investigated the precise roles of Sirt1 in HIF-1α and HIF-2α regulations. Immunological analyses revealed that HIF-1α K674 and HIF-2α K741 are acetylated by PCAF and CBP, respectively, but are deacetylated commonly by Sirt1. In the Gal4 reporter systems, Sirt1 was found to repress HIF-1α activity constantly in ten cancer cell-lines but to regulate HIF-2α activity cell type-dependently. Moreover, Sirt1 determined cell growth under hypoxia depending on HIF-1α and HIF-2α. Under hypoxia, Sirt1 promoted cell proliferation of HepG2, in which Sirt1 differentially regulates HIF-1α and HIF-2α. In contrast, such an effect of Sirt1 was not shown in HCT116, in which Sirt1 inactivates both HIF-1α and HIF-2α because conflicting actions of HIF-1α and HIF-2α on cell growth may be offset. Our results provide a better understanding of the roles of Sirt1 in HIF-mediated hypoxic responses and also a basic concept for developing anticancer strategy targeting Sirt1.
authors.affiliation: Departments of Biomedical Sciences and Pharmacology, Ischemic/Hypoxic Disease Institute, Cancer Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Haejin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Departments of Biomedical Sciences and Pharmacology, Ischemic/Hypoxic Disease Institute, Cancer Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Shin
authors.affiliation: Departments of Biomedical Sciences and Pharmacology, Ischemic/Hypoxic Disease Institute, Cancer Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Departments of Biomedical Sciences and Pharmacology, Ischemic/Hypoxic Disease Institute, Cancer Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Yang-Sook
authors.initials: YS
authors.lastname: Chun
authors.affiliation: Departments of Biomedical Sciences and Pharmacology, Ischemic/Hypoxic Disease Institute, Cancer Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea. Electronic address: parkjw@snu.ac.kr.
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008239:Lysine; D034741:RNA, Small Interfering; D056564:Sirtuin 1; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C447939:SIRT1 protein, human
keywords: Hypoxia; Hypoxia-inducible factors; Lysine acetylation; Sirtuin 1; Transcriptional activity