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1、14HDACInhibitorsAnEmergingAnticancerTherapeuticStrategyPaulKwon,MeierHsu,DaliaCohen,PhD,andPeterAtadja,PhDCONTENTSSUMMARYHISTONESANDTHEREMODELINGOFCHROMATINSTRUCTUREHISTONEACETYLATION,GENEREGULATION,ANDCANCERHDACINHIBITORSANTICANCEREFFECTSOFHDACINHIBITORSCURRENTISSUESANDFUTUREOUT
2、LOOKREFERENCESSUMMARYCoordinatedandtighttranscriptionalregulationofgeneticinformationisvitalformaintenanceofnormalcellgrowthanddifferentiation.Canceristypifiedbyinappropriategeneexpression—aberrantexpressionofgenesassociatedwithincreasedcellularproliferationandsurvival(e.g.,onco-
3、genes),aswellasalterationsingenesencodingtumorsuppressorproteins.Therefore,targetingthegeneexpressionmachinerytorestoreitsnormalcypromisestobeausefulanticancertherapeuticstrategy.Inthepast,targetingFrom:CancerDrugDiscoveryandDevelopmentHistoneDeacetylases:TranscriptionalRegulatio
4、nandOtherCellularFunctionsEditedby:E.Verdin©HumanaPressInc.,Totowa,NJ315316Kwonetal.theDNAbindingmultiproteintranscriptionfactorswithreasonablepotencyandspecificityhasbeenchallengingowingtodifficultiesindis-ruptingprotein-proteinandprotein-DNAinteractions.However,recentstudiessho
5、wedthatepigeneticmodificationsbyenzymesplaykeyrolesinregulatinggeneexpression,providinganopportunitytotargetsuchenzymeswithsmallmoleculesfortherapeuticpurposes.Histonedeacety-lases(HDACs)canregulategeneexpressionbydeacetylatinghistones,leadingtorepressedchromatinstructure.Inaddit
6、ion,HDACscantargetnonhistonesubstrates,includingseveraloncoproteinsandtumorsuppres-sors.ThusabnormalHDACactivitymayleadtoaberrantgeneexpressionaswellasperturbationincriticalpathways.HDACinhibitorshavedemon-stratedefficacyinavarietyofsolidandhematologicalmalignanciesinearlyclinica
7、ltrials.Thecurrentreviewfocusesontheemergingutilityofhistonedeacetylaseinhibitionasananticancertherapeuticstrategy.KeyWords:HDAC,HDACinhibitor,histone,acetylation,deacetylation,cancer,therapy,smallmolecule.HISTONESANDTHEREMODELINGOFCHROMATINSTRUCTUREIneukaryoticcells,DNAispackage
8、dintochromatin.Thepackagingunitinthechro
