Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia

• Published in: The Journal of biological chemistry Vol. 286; no. 18; pp. 16101 - 16108
• Main Authors: Cenik, Basar, Sephton, Chantelle F, Dewey, Colleen M, Xian, Xunde, Wei, Shuguang, Yu, Kimberley, Niu, Wenze, Coppola, Giovanni, Coughlin, Sarah E, Lee, Suzee E, Dries, Daniel R, Almeida, Sandra, Geschwind, Daniel H, Gao, Fen-Biao, Miller, Bruce L, Farese, Jr, Robert V, Posner, Bruce A, Yu, Gang, Herz, Joachim
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 06.05.2011
• Subjects: Dose-Response Relationship, Drug; Frontotemporal Dementia - drug therapy; Frontotemporal Dementia - metabolism; HEK293 Cells; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; Intercellular Signaling Peptides and Proteins - biosynthesis; Neurobiology; Progranulins; Transcription, Genetic - drug effects; Up-Regulation - drug effects; Vorinostat
• ISSN: 1083-351X; 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.193433

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.