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
PubMed link: 
21454553
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.