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

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. Farese, Bruce A. Posner, Gang Yu, Joachim Herz

Research output: Contribution to journalArticle

104 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)16101-16108
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number18
DOIs
StatePublished - May 6 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Cenik, B., Sephton, C. F., Dewey, C. M., Xian, X., Wei, S., Yu, K., Niu, W., Coppola, G., Coughlin, S. E., Lee, S. E., Dries, D. R., Almeida, S., Geschwind, D. H., Gao, F. B., Miller, B. L., Farese, R. V., Posner, B. A., Yu, G., & Herz, J. (2011). Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: Rational therapeutic approach to frontotemporal dementia. Journal of Biological Chemistry, 286(18), 16101-16108. https://doi.org/10.1074/jbc.M110.193433