title: The epigenetic regulation of HIF-1α by SIRT1 in MPP(+) treated SH-SY5Y cells.
abstract: Both silent information regulator 1 (SIRT1) and hypoxia inducible factor 1 (HIF-1) have been found to play important roles in the pathophysiology of Parkinson's disease (PD). However, their mechanisms and their relationship still require further study. In the present study, we focused on the change and relationship of SIRT1 and HIF-1α in PD. PD cell models were established by using methyl-4-phenylpyridinium (MPP(+)), which induced inhibition of cell proliferation, cell cycle arrest and apoptosis. We found that the expression of HIF-1α and its target genes VEGFA and LDHA increased and that SIRT1 expression was inhibited in MPP(+) treated cells. With further analysis, we found that the acetylation of H3K14 combined with the HIF-1α promoter was dramatically increased in cells treated with MPP(+), which resulted in the transcriptional activation of HIF-1α. Moreover, the acetylation of H3K14 and the expression of HIF-1α increased when SIRT1 was knocked down, suggesting that SIRT1 was involved in the epigenetic regulation of HIF-1α. At last, phenformin, another mitochondrial complex1 inhibitor, was used to testify that the increased HIF-1a was not due to off target effects of MPP(+). Therefore, our results support a link between PD and SIRT1/HIF-1α signaling, which may serve as a clue for understanding PD.
authors.affiliation: Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China.
authors.forename: Su-Yan
authors.initials: SY
authors.lastname: Dong
authors.affiliation: Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Guo
authors.affiliation: Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China.
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Cui
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, USA.
authors.forename: Sheng-Han
authors.initials: SH
authors.lastname: Kuo
authors.affiliation: Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, PR China. Electronic address: liute1979@126.com.
authors.forename: Te
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China. Electronic address: yunchw@medmail.com.cn.
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Wu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D015655:1-Methyl-4-phenylpyridinium
keywords: Acetylation; Epigenetics; H3K14; Hypoxia inducible factor-1; Parkinson's disease; Silent information regulator 1