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

Publication Type:

Journal Article

Source:

J Biol Chem, Volume 286, Issue 18, p.16101-8 (2011)

Keywords:

Dose-Response Relationship, Drug, Frontotemporal Dementia, HEK293 Cells, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Intercellular Signaling Peptides and Proteins, Transcription, Genetic, Up-Regulation

Abstract:

<p>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.</p>

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