title: SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1α (HIF-1α) via direct interactions during hypoxia.
abstract: Upon shift to a hypoxic environment, cellular HIF-1α protein is stabilized, with a rapid decline in oxygen-sensitive hydroxylation. Several additional post-translational modifications of HIF-1α are critical in controlling protein stability during hypoxia. In the present study, we showed that SIRT1 stabilizes HIF-1α via direct binding and deacetylation during hypoxia. SIRT1 depletion or inactivation led to reduced hypoxic HIF-1α accumulation, accompanied by an increase in HIF-1α acetylation. Impaired HIF-1α accumulation was recovered upon inhibition of 26S proteasome activity, indicating that SIRT1 is essential for HIF-1α stabilization during hypoxia. Consistently, HIF-1α accumulation was enhanced upon overexpression of wild-type SIRT1, but not its dominant-negative form. SIRT1-mediated accumulation of HIF-1α protein led to increased expression of HIF-1α target genes, including VEGF, GLUT1 and MMP2, and ultimate promotion of cancer cell invasion. These findings collectively imply that hypoxic HIF-1α stabilization requires SIRT1 activation. Furthermore, SIRT1 protection of HIF-1α from acetylation may be a prerequisite for stabilization and consequent enhancement of cell invasion.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, South Korea; Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul 136-713, South Korea.
authors.forename: Hyun-Yoo
authors.initials: HY
authors.lastname: Joo
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Kyung Hee University, Seoul 130-872, South Korea.
authors.forename: Miyong
authors.initials: M
authors.lastname: Yun
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Jaemin
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Eun-Ran
authors.initials: ER
authors.lastname: Park
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Seon Rang
authors.initials: SR
authors.lastname: Woo
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Jin Kyu
authors.initials: JK
authors.lastname: Jung
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Yong-Min
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Physiology, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Joong-Jean
authors.initials: JJ
authors.lastname: Park
authors.affiliation: Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul 136-713, South Korea. Electronic address: joonkim@korea.ac.kr.
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, South Korea. Electronic address: khlee@kirams.re.kr.
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D001483:Base Sequence; D015687:Cell Hypoxia; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Deacetylation; HIF-1α; Interaction; Invasion; SIRT1; Stabilization