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

被引：120

作者：

Cenik, Basar ^{[2
]}

Sephton, Chantelle F.

Dewey, Colleen M.

Xian, Xunde ^{[2
]}

Wei, Shuguang ^{[4
]}

Yu, Kimberley

Niu, Wenze

Coppola, Giovanni ^{[5
]}

Coughlin, Sarah E. ^{[6
]}

Lee, Suzee E. ^{[7
]}

Dries, Daniel R. ^{[1
]}

Almeida, Sandra ^{[10
]}

Geschwind, Daniel H. ^{[5
]}

Gao, Fen-Biao ^{[10
]}

Miller, Bruce L. ^{[7
]}

Farese, Robert V., Jr. ^{[6
,8
,9
]}

Posner, Bruce A. ^{[4
]}

Yu, Gang ^{[1
]}

Herz, Joachim ^{[1
,2
,3
]}

机构：

[1] Univ Texas SW Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA

[2] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA

[3] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

[5] Univ Calif Los Angeles, Program Neurogenet, Dept Neurol, David Geffen Sch Med, Los Angeles, CA 90024 USA

[6] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA

[7] Univ Calif San Francisco, Memory & Aging Ctr, San Francisco, CA 94143 USA

[8] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[9] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA

[10] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01605 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2011年 / 286卷 / 18期

基金：

美国国家卫生研究院;

关键词：

HISTONE DEACETYLASE INHIBITORS; LOBAR DEGENERATION; HDAC INHIBITORS; IN-VITRO; RESVERATROL; MUTATIONS; DISEASE; VIVO; ACETYLATION; ACTIVATION;

D O I：

10.1074/jbc.M110.193433

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：16101 / 16108

页数：8

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