title: Dimethyl fumarate inhibits the expression and function of hypoxia-inducible factor-1α (HIF-1α).
abstract: Osteocyte hypoxia has been induced by skeletal unloading and fracture. Hypoxia-dependent regulation of gene expression is mediated by hypoxia-sensitive transcription factors such as hypoxia-inducible factor-1α (HIF-1α). Dimethyl fumarate (DMF) is a recently approved first-line therapy for multiple sclerosis. However, the role of DMF in regulating HIF-1α expression and function has not been evaluated. In this study, we found that DMF inhibited hypoxia-induced expression of HIF-1α and its target genes such as interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) in MC3T3 E1 cells. Mechanistically, DMF promoted HIF-1α degradation in a proteasome-dependent but von Hippel-Lindau (VHL) protein-independent manner. Importantly, we found that DMF disrupted the interaction between HIF-1α and its chaperone heat shock protein 90 (Hsp90) but promoted the interaction between HIF-1α and the receptor of activated protein kinase C (RACK1). These data suggest that DMF might promote degradation of HIF-1α by affecting its folding and maturation. Based on these observations, we conclude that DMF is a novel inhibitor of HIF-1α.
authors.affiliation: Department of Orthopaedics, Qilu Hospital of Shandong University, China; Department of Orthopaedics, Yidu Central Hospital of Weifang, China.
authors.forename: Guangzong
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Yidu Central Hospital of Weifang, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Yidu Central Hospital of Weifang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.affiliation: Department of Orthopaedics, Qilu Hospital of Shandong University, China. Electronic address: yzchen6501@hotmail.com.
authors.forename: Yunzhen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Yidu Central Hospital of Weifang, China.
authors.forename: Huazhuang
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Yidu Central Hospital of Weifang, China.
authors.forename: Kehai
authors.initials: K
authors.lastname: Gao
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D005650:Fumarates; D018841:HSP90 Heat-Shock Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D009479:Neuropeptides; D061988:Proteasome Inhibitors; C090294:RACK1 protein, mouse; D012333:RNA, Messenger; D000075370:Receptors for Activated C Kinase; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000069462:Dimethyl Fumarate
keywords: Heat shock protein 90 (Hsp90); Hypoxia; Hypoxia-inducible factor-1α (HIF-1α); Proteasomal degradation; The receptor of activated protein kinase C (RACK1)