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, 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, Robert V. Jr.; Posner, Bruce A.; Yu, Gang; and Herz, Joachim, "Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia" (2011). Neurology Publications and Presentations. 415.
https://escholarship.umassmed.edu/neuro_pp/415