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

TitleSuberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia.
Publication TypeJournal Article
Year of Publication2011
AuthorsCenik, 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
JournalThe Journal of biological chemistry
Volume286
Issue18
Pagination16101-8
Date Published2011 May 6
ISSN1083-351X
KeywordsDose-Response Relationship, Drug, Frontotemporal Dementia, HEK293 Cells, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Intercellular Signaling Peptides and Proteins, Transcription, Genetic, Up-Regulation
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.

DOI10.1111/j.1460-9568.2012.08054.x
Alternate JournalJ. Biol. Chem.