title: Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors.
abstract: Histone deacetylase inhibitors (HDACis) inhibit tumor cell growth and survival, possibly through their ability to regulate the expression of specific proliferative and/or apoptotic genes. However, the HDACi-regulated genes necessary and/or sufficient for their biological effects remain undefined. We demonstrate that the HDACis suberoylanilide hydroxamic acid (SAHA) and depsipeptide regulate a highly overlapping gene set with at least 22% of genes showing altered expression over a 16-h culture period. SAHA and depsipeptide coordinately regulated the expression of several genes within distinct apoptosis and cell cycle pathways. Multiple genes within the Myc, type beta TGF, cyclin/cyclin-dependent kinase, TNF, Bcl-2, and caspase pathways were regulated in a manner that favored induction of apoptosis and decreased cellular proliferation. APAF-1, a gene central to the intrinsic apoptotic pathway, was induced by SAHA and depsipeptide and shown to be important, but not essential, for HDACi-induced cell death. Overexpression of p16(INK4A) and arrest of cells in G(1) can suppress HDACi-mediated apoptosis. Although p16(INK4A) did not affect the genome-wide transcription changes mediated by SAHA, a small number of apoptotic genes, including BCLXL and B-MYB, were differentially regulated in a manner consistent with attenuated HDACi-mediated apoptosis in arrested cells. We demonstrate that different HDACi alter transcription of a large and common set of genes that control diverse molecular pathways important for cell survival and proliferation. The ability of HDACi to target multiple apoptotic and cell proliferation pathways may provide a competitive advantage over other chemotherapeutic agents because suppression/loss of a single pathway may not confer resistance to these agents.
authors.affiliation: The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, Victoria, Australia.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Peart
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Ryan K
authors.initials: RK
authors.lastname: van Laar
authors.forename: David D
authors.initials: DD
authors.lastname: Bowtell
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
authors.forename: Paul A
authors.initials: PA
authors.lastname: Marks
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Holloway
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D049109:Cell Proliferation; D002478:Cells, Cultured; D047630:Depsipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011506:Proteins; D034741:RNA, Small Interfering; D000077337:Vorinostat
references.citation: J Biol Chem. 2000 Oct 27;275(43):33416-26
references.pmid: 10924506
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):673-8
references.pmid: 15637150
references.citation: Mol Cancer Ther. 2003 Feb;2(2):151-63
references.pmid: 12589032
references.citation: Cell Death Differ. 2004 Apr;11(4):381-9
references.pmid: 14685163
references.citation: J Cell Physiol. 2001 May;187(2):155-65
references.pmid: 11267995
references.citation: Cancer Cell. 2004 Jun;5(6):575-85
references.pmid: 15193260
references.citation: Oncogene. 1999 Nov 25;18(50):7016-25
references.pmid: 10597302
references.citation: Kidney Int. 2000 Mar;57(3):949-58
references.pmid: 10720948
references.citation: Annu Rev Cell Dev Biol. 2000;16:653-99
references.pmid: 11031250
references.citation: J Biol Chem. 2001 Jun 15;276(24):10984-9
references.pmid: 11441822
references.citation: Oncogene. 2004 Oct 21;23(49):8135-45
references.pmid: 15361828
references.citation: Mol Cell Biol. 1994 Apr;14(4):2352-60
references.pmid: 8139540
references.citation: Cell. 2002 Jan 25;108(2):153-64
references.pmid: 11832206
references.citation: Org Lett. 2003 Aug 21;5(17):3053-6
references.pmid: 12916979
references.citation: Cell Death Differ. 1999 Nov;6(11):1081-6
references.pmid: 10578177
references.citation: Gene Expr. 1996;5(4-5):245-53
references.pmid: 8723390
references.citation: Cancer Res. 1999 Sep 1;59(17):4392-9
references.pmid: 10485488
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10833-8
references.pmid: 11535817
references.citation: Cell Death Differ. 2003 Mar;10(3):269-77
references.pmid: 12700627
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10014-9
references.pmid: 10954755
references.citation: Adv Cancer Res. 2004;91:137-68
references.pmid: 15327890
references.citation: Am J Physiol Gastrointest Liver Physiol. 2000 Apr;278(4):G513-21
references.pmid: 10762604
references.citation: Oncogene. 1998 Dec 24;17(25):3261-70
references.pmid: 9916988
references.citation: Cancer Res. 2000 Aug 15;60(16):4561-72
references.pmid: 10969808
references.citation: Genes Cells. 2002 Dec;7(12):1191-204
references.pmid: 12485160
references.citation: Cancer Res. 2003 Aug 1;63(15):4460-71
references.pmid: 12907619
references.citation: Oncogene. 2003 Dec 8;22(56):8961-82
references.pmid: 14663476
references.citation: Nat Rev Immunol. 2003 Sep;3(9):745-56
references.pmid: 12949498
references.citation: Science. 2002 Aug 23;297(5585):1352-4
references.pmid: 12193789
references.citation: Cell. 1998 Sep 18;94(6):739-50
references.pmid: 9753321
references.citation: Genome Biol. 2004;5(10):R80
references.pmid: 15461798
references.citation: Mol Pharmacol. 2001 Oct;60(4):828-37
references.pmid: 11562446
references.citation: J Biol Chem. 1998 Oct 30;273(44):29066-71
references.pmid: 9786912
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):540-5
references.pmid: 14695887
references.citation: Apoptosis. 2003 Jun;8(3):229-36
references.pmid: 12766483
references.citation: Mol Cell Neurosci. 2002 Aug;20(4):553-62
references.pmid: 12213439
references.citation: Nat Rev Cancer. 2002 Sep;2(9):647-56
references.pmid: 12209154
references.citation: Nat Rev Drug Discov. 2002 Apr;1(4):287-99
references.pmid: 12120280
references.citation: Cancer Res. 2002 Sep 1;62(17):4916-21
references.pmid: 12208741
references.citation: Mol Cell Biol. 2003 Sep;23(17):6174-86
references.pmid: 12917339
references.citation: Nature. 2001 Jan 11;409(6817):207-11
references.pmid: 11196646
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18030-5
references.pmid: 15596714
references.citation: Stat Appl Genet Mol Biol. 2004;3:Article3
references.pmid: 16646809
references.citation: Cancer Gene Ther. 2001 Oct;8(10):740-50
references.pmid: 11687897
references.citation: Nat Immunol. 2001 Mar;2(3):242-7
references.pmid: 11224524