Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia.
|Title||Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia.|
|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Cenik, B, Sephton CF, Dewey CM, Xian X, Wei S, Yu K, Niu W, Coppola G, Coughlin SE, Lee SE, Dries DR, Almeida S, Geschwind DH, Gao F-B, Miller BL, Farese RV, Posner BA, Yu G, Herz J|
|Journal||The Journal of biological chemistry|
|Date Published||2011 May 6|
|Keywords||Dose-Response Relationship, Drug, Frontotemporal Dementia, HEK293 Cells, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Intercellular Signaling Peptides and Proteins, Transcription, Genetic, Up-Regulation|
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.
|Alternate Journal||J. Biol. Chem.|