title: Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia.
abstract: Progranulin (GRN) haploinsufficiency is a frequent cause of familial frontotemporal dementia, a currently untreatable progressive neurodegenerative disease. By chemical library screening, we identified suberoylanilide hydroxamic acid (SAHA), a Food and Drug Administration-approved histone deacetylase inhibitor, as an enhancer of GRN expression. SAHA dose-dependently increased GRN mRNA and protein levels in cultured cells and restored near-normal GRN expression in haploinsufficient cells from human subjects. Although elevation of secreted progranulin levels through a post-transcriptional mechanism has recently been reported, this is, to the best of our knowledge, the first report of a small molecule enhancer of progranulin transcription. SAHA has demonstrated therapeutic potential in other neurodegenerative diseases and thus holds promise as a first generation drug for the prevention and treatment of frontotemporal dementia.
authors: Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9111, USA.
authors: Basar
authors: B
authors: Cenik
authors: Chantelle F
authors: CF
authors: Sephton
authors: Colleen M
authors: CM
authors: Dewey
authors: Xunde
authors: X
authors: Xian
authors: Shuguang
authors: S
authors: Wei
authors: Kimberley
authors: K
authors: Yu
authors: Wenze
authors: W
authors: Niu
authors: Giovanni
authors: G
authors: Coppola
authors: Sarah E
authors: SE
authors: Coughlin
authors: Suzee E
authors: SE
authors: Lee
authors: Daniel R
authors: DR
authors: Dries
authors: Sandra
authors: S
authors: Almeida
authors: Daniel H
authors: DH
authors: Geschwind
authors: Fen-Biao
authors: FB
authors: Gao
authors: Bruce L
authors: BL
authors: Miller
authors: Robert V
authors: RV
authors: Farese
authors: Bruce A
authors: BA
authors: Posner
authors: Gang
authors: G
authors: Yu
authors: Joachim
authors: J
authors: Herz
mesh_terms: D004305:Dose-Response Relationship, Drug; D057180:Frontotemporal Dementia / Q000188:drug therapy* / Q000378:metabolism; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D000077153:Progranulins; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*; D000077337:Vorinostat
chemical_list: C492314:GRN protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D000077337:Vorinostat