Suberoylanilide Hydroxamic Acid (Vorinostat) Up-regulates Progranulin Transcription: RATIONAL THERAPEUTIC APPROACH TO FRONTOTEMPORAL DEMENTIA.

Journal: 
J Biol Chem
Publication Year: 
2011
Authors: 
Basar Cenik , Chantelle F Sephton , Colleen M Dewey , Xunde Xian , Shuguang Wei , Kimberley Yu , Wenze Niu , Giovanni Coppola , Sarah E Coughlin , Suzee E Lee , Daniel R Dries , Sandra Almeida , Daniel H Geschwind , Fen-Biao Gao , Bruce L Miller , Robert V Jr Farese , Bruce A Posner , Gang Yu , Joachim Herz
Public Summary: 
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.
Scientific 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.

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