title: SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation.
abstract: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1α stimulates glycolytic energy production and promotes tumour growth. Sirtuins are NAD(+)-dependent protein deacetylases that regulate cellular metabolism in response to stress; however, their involvement in the hypoxic response remains unclear. In this study, it is shown that SIRT2-mediated deacetylation of HIF-1α regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1α under hypoxic conditions, whereas HIF-1α protein levels were high in SIRT2-deficient cells. SIRT2 directly interacted with HIF-1α and deacetylated Lys709 of HIF-1α. Deacetylation of HIF-1α by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1α stability, and increased HIF-1α hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD(+)/NADH ratio led to the degradation of HIF-1α by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These findings suggest that SIRT2-mediated HIF-1α deacetylation is critical for the destablization of HIF-1α and the hypoxic response of tumour cells.
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: K-S
authors.initials: KS
authors.lastname: Seo
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Park
authors.affiliation: 1] Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Heo
authors.affiliation: 1] Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Jing
authors.affiliation: 1] Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Han
authors.affiliation: KT&G Life Sciences Corp. R&D Center, Suwon, Korea.
authors.forename: K-N
authors.initials: KN
authors.lastname: Min
authors.affiliation: National Research Laboratory of Vascular Biology and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: C
authors.initials: C
authors.lastname: Kim
authors.affiliation: National Research Laboratory of Vascular Biology and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: G Y
authors.initials: GY
authors.lastname: Koh
authors.affiliation: 1] Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea [3] Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Lim
authors.affiliation: Diatech Korea Co., Ltd, Seoul, Korea.
authors.forename: G-Y
authors.initials: GY
authors.lastname: Kang
authors.affiliation: Department of Pathology, St. Mary's Hospital, The Catholic University, Daejeon, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Uee Lee
authors.affiliation: Korea Research Institute of Standard and Science, Daejeon, Korea.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Yim
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: M
authors.initials: M
authors.lastname: Shong
authors.affiliation: KT&G Life Sciences Corp. R&D Center, Suwon, Korea.
authors.forename: T-H
authors.initials: TH
authors.lastname: Kwak
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: G R
authors.initials: GR
authors.lastname: Kweon
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009243:NAD / Q000378:metabolism; D064828:Prolyl Hydroxylases / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D034622:RNA Interference; D034741:RNA, Small Interfering; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D009243:NAD; D064828:Prolyl Hydroxylases; C474199:SIRT2 protein, human; D056565:Sirtuin 2