Title
Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia
UMMS Affiliation
Department of Neurology
Publication Date
2011-05-06
Document Type
Article
Subjects
Dose-Response Relationship, Drug; Frontotemporal Dementia; HEK293 Cells; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Intercellular Signaling Peptides and Proteins; Transcription, Genetic; Up-Regulation
Disciplines
Neurology | Neuroscience and Neurobiology
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.
DOI of Published Version
10.1074/jbc.M110.193433
Source
J Biol Chem. 2011 May 6;286(18):16101-8. Epub 2011 Mar 23. Link to article on publisher's site
Journal/Book/Conference Title
The Journal of biological chemistry
Related Resources
PubMed ID
21454553
Repository Citation
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, Miller BL, Farese RV, Posner BA, Yu G, Herz J. (2011). Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. Neurology Publications. https://doi.org/10.1074/jbc.M110.193433. Retrieved from https://escholarship.umassmed.edu/neuro_pp/415