title: Histone deacetylase inhibitors SAHA and sodium butyrate block G1-to-S cell cycle progression in neurosphere formation by adult subventricular cells.
abstract: BACKGROUND
  Histone deacetylases (HDACs) are enzymes that modulate gene expression and cellular processes by deacetylating histones and non-histone proteins. While small molecule inhibitors of HDAC activity (HDACi) are used clinically in the treatment of cancer, pre-clinical treatment models suggest they also exert neuroprotective effects and stimulate neurogenesis in neuropathological conditions. However, the direct effects of HDACi on cell cycle progression and proliferation, two properties required for continued neurogenesis, have not been fully characterized in adult neural stem cells (NSCs). In this study, we examined the effects of two broad class I and class II HDACi on adult mouse NSCs, the hydroxamate-based HDACi suberoylanilide hydroxamic acid (vorinostat, SAHA) and the short chain fatty acid HDACi sodium butyrate.
  
  
  RESULTS
  We show that both HDACi suppress the formation of neurospheres by adult mouse NSCs grown in proliferation culture conditions in vitro. DNA synthesis is significantly inhibited in adult mouse NSCs exposed to either SAHA or sodium butyrate and inhibition is associated with an arrest in the G1 phase of the cell cycle. HDACi exposure also resulted in transcriptional changes in adult mouse NSCs. Cdk inhibitor genes p21 and p27 transcript levels are increased and associated with elevated H3K9 acetylation levels at proximal promoter regions of p21 and p27. mRNA levels for notch effector Hes genes and Spry-box stem cell transcription factors are downregulated, whereas pro-neural transcription factors Neurog1 and Neurod1 are upregulated. Lastly, we show HDAC inhibition under proliferation culture conditions leads to long-term changes in cell fate in adult mouse NSCs induced to differentiate in vitro.
  
  
  CONCLUSIONS
  SAHA and sodium butyrate directly regulate cdk inhibitor transcription to control cell cycle progression in adult mouse NSCs. HDAC inhibition results in G1 arrest in adult mouse NSCs and transcriptional changes associated with activation of neuronal lineage commitment programs and a reduction of stem/progenitor state. Changes in differentiated cell state in adult mouse NSCs treated with HDACi under proliferation culture conditions suggests an intrinsic relationship between multipotency, cell cycle progression and HDAC activity in these cells.
authors: Department of Anatomy, Physiology and Genetics, Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors: Qiong
authors: Q
authors: Zhou
authors: Clifton L
authors: CL
authors: Dalgard
authors: Christopher
authors: C
authors: Wynder
authors: Martin L
authors: ML
authors: Doughty
references: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16659-64
references: 15537713
references: Nature. 2009 Mar 26;458(7237):529-33
references: 19212323
references: Nat Neurosci. 2009 Jul;12(7):829-38
references: 19503085
references: J Neurosci. 2009 Mar 4;29(9):2824-32
references: 19261878
references: Mol Cell Neurosci. 2010 Oct;45(2):121-31
references: 20599619
references: Neuroscience. 2009 Sep 29;163(1):1-8
references: 19531374
references: Nat Neurosci. 2010 Nov;13(11):1338-44
references: 20975758
references: Nature. 2006 Aug 17;442(7104):823-6
references: 16799564
references: J Biol Chem. 2010 Aug 13;285(33):25516-21
references: 20554530
references: Biomed Pharmacother. 2010 Dec;64(10):733-40
references: 20970954
references: Cell Stem Cell. 2010 Jul 2;7(1):9-10
references: 20621042
references: Exp Brain Res. 2007 Feb;176(4):672-8
references: 17216146
references: Brain Res Mol Brain Res. 1998 Oct 30;61(1-2):203-6
references: 9795219
references: Nature. 2007 May 10;447(7141):178-82
references: 17468743
references: J Cell Biochem. 2009 Jul 1;107(4):600-8
references: 19459166
references: Genes Dev. 2010 Mar 1;24(5):455-69
references: 20194438
references: Nature. 2005 Oct 6;437(7060):894-7
references: 16208373
references: J Cell Physiol. 2005 Jan;202(1):87-99
references: 15389542
references: J Biol Chem. 2009 Mar 13;284(11):6998-7006
references: 19139101
references: J Pharmacol Exp Ther. 2007 Jun;321(3):892-901
references: 17371805
references: Cancer Lett. 2009 Aug 8;280(2):160-7
references: 19342155
references: Nat Rev Drug Discov. 2008 Oct;7(10):854-68
references: 18827828
references: Nat Neurosci. 2003 Jan;6(1):21-7
references: 12469128
references: J Clin Oncol. 2005 Jun 10;23(17):3923-31
references: 15897550
references: J Neurochem. 2009 Aug;110(4):1226-40
references: 19549282
references: Development. 2005 Jan;132(2):335-44
references: 15604099
references: J Neurosci. 2010 Aug 4;30(31):10484-92
references: 20685991
references: Anticancer Drugs. 2002 Jan;13(1):1-13
references: 11914636
references: Stem Cells. 2008 Apr;26(4):920-6
references: 18203677
references: J Neurosci. 2010 Jun 9;30(23):7961-74
references: 20534844
references: EMBO J. 2010 Aug 4;29(15):2586-97
references: 20571512
references: Appl Microbiol Biotechnol. 2007 Jun;75(3):499-514
references: 17377788
references: Mol Cell Biol. 2010 Mar;30(5):1171-81
references: 20028735
references: Cell. 2003 May 30;113(5):631-42
references: 12787504
references: Nat Biotechnol. 2008 Jul;26(7):795-7
references: 18568017
references: EMBO J. 2002 Jun 3;21(11):2672-81
references: 12032080
references: Mol Psychiatry. 2008 Mar;13(3):285-92
references: 17968353
references: J Biol Chem. 2008 May 9;283(19):12686-90
references: 18356165
references: J Neurosci. 2007 Jun 6;27(23):6128-40
references: 17553985
references: Cell Cycle. 2005 Apr;4(4):549-51
references: 15738652
references: Cancer Lett. 2009 Aug 8;280(2):177-83
references: 19362413
references: Nature. 2005 Oct 27;437(7063):1370-5
references: 16251967
references: Biol Psychiatry. 2007 Jul 1;62(1):55-64
references: 16945350
references: Int J Biochem Cell Biol. 2007;39(7-8):1367-74
references: 17412634
references: Stem Cells Dev. 2009 May;18(4):573-81
references: 18694296
references: Neurosci Lett. 2009 Dec 31;467(3):212-6
references: 19835929
references: Neuron Glia Biol. 2010 May;6(2):93-107
references: 20388229