title: Involvement of SIRT1 in hypoxic down-regulation of c-Myc and β-catenin and hypoxic preconditioning effect of polyphenols.
abstract: SIRT1 has been found to function as a Class III deacetylase that affects the acetylation status of histones and other important cellular nonhistone proteins involved in various cellular pathways including stress responses and apoptosis. In this study, we investigated the role of SIRT1 signaling in the hypoxic down-regulations of c-Myc and β-catenin and hypoxic preconditioning effect of the red wine polyphenols such as piceatannol, myricetin, quercetin and resveratrol. We found that the expression of SIRT1 was significantly increased in hypoxia-exposed or hypoxic preconditioned HepG2 cells, which was closely associated with the up-regulation of HIF-1α and down-regulation of c-Myc and β-catenin expression via deacetylation of these proteins. In addition, blockade of SIRT1 activation using siRNA or amurensin G, a new potent SIRT1 inhibitor, abolished hypoxia-induced HIF-1α expression but increased c-Myc and β-catenin expression. SIRT1 was also found to stabilize HIF-1α protein and destabilize c-Myc, β-catenin and PHD2 under hypoxia. We also found that myricetin, quercetin, piceatannol and resveratrol up-regulated HIF-1α and down-regulated c-Myc, PHD2 and β-catenin expressions via SIRT1 activation, in a manner that mimics hypoxic preconditioning. This study provides new insights of the molecular mechanisms of hypoxic preconditioning and suggests that polyphenolic SIRT1 activators could be used to mimic hypoxic/ischemic preconditioning.
authors.affiliation: Department of Biochemistry, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Hong
authors.forename: Jun-Ik
authors.initials: JI
authors.lastname: Park
authors.forename: Mi-Ju
authors.initials: MJ
authors.lastname: Kim
authors.forename: Hak-Bong
authors.initials: HB
authors.lastname: Kim
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Trong Tuan
authors.initials: TT
authors.lastname: Dao
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Oh
authors.forename: Chi-Dug
authors.initials: CD
authors.lastname: Kang
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D015687:Cell Hypoxia / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D059808:Polyphenols / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D059808:Polyphenols; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051176:beta Catenin; C447939:SIRT1 protein, human; D056564:Sirtuin 1