title: AK-1, a SIRT2 inhibitor, destabilizes HIF-1α and diminishes its transcriptional activity during hypoxia.
abstract: Sirtuin family proteins are involved in the regulation of hypoxic responses which are primarily dependent on a hypoxia-inducible factor (HIF). However, few studies have examined the use of sirtuin inhibitors to regulate HIF. The present study examined the effect of a SIRT2-specific inhibitor, AK-1, on hypoxic responses. Under hypoxic conditions, AK-1 increased the ubiquitination of HIF-1α in a VHL-dependent manner, leading to the degradation of HIF-1α via a proteasomal pathway. Downregulation of HIF-1α expression reduced its transcriptional activity and, eventually, reduced the expression of BNIP3, one of HIF-1 target genes, in AK-1-treated cells. These data demonstrate that SIRT2 inhibition attenuates hypoxic responses, and that SIRT2 inhibitors may have potential as treatments for hypoxia-associated pathological conditions.
authors.affiliation: Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: So Dam
authors.initials: SD
authors.lastname: Lee
authors.affiliation: Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Wootae
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Anatomy and Neurobiology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: jekim@khu.ac.kr.
authors.forename: Ja-Eun
authors.initials: JE
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015687:Cell Hypoxia; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D059016:Tumor Microenvironment; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C000608812:AK-1 compound; D000970:Antineoplastic Agents; C090121:BNIP3 protein, human; D001549:Benzamides; C497442:HIF1A protein, human; D056572:Histone Deacetylase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D046988:Proteasome Endopeptidase Complex; C474199:SIRT2 protein, human; D056565:Sirtuin 2; C497446:VHL protein, human
keywords: AK-1; Cancer; HIF-1α; Hypoxia; SIRT2