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Class I and Class II Histone Deacetylases Are Potential Therapeutic Targets for Treating Pancreatic Cancer.doc

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Class I and Class II Histone Deacetylases Are Potential Therapeutic Targets for Treating Pancreatic Cancer

ClassIandClassIIHistoneDeacetylasesArePotential TherapeuticTargetsforTreatingPancreaticCancer GuanWang1,JingHe1,JianyunZhao1,WentingYun1,ChengzhiXie1,4,7,JeffreyW.Taub2,3,4,AsfarAzmi7, RamziM.Mohammad7,YanDong1,5,WeiKong1,6,YingjieGuo1*,YubinGe1,4,7* 1TheStateEngineeringLaboratoryofAIDSVaccine,CollegeofLifeScience,JilinUniversity,Changchun,China,2DivisionofPediatricHematology/Oncology,Children’s HospitalofMichigan,Detroit,Michigan,UnitedStatesofAmerica,3DepartmentofPediatrics,WayneStateUniversitySchoolofMedicine,Detroit,Michigan,UnitedStates ofAmerica,4MolecularTherapeuticsProgram,BarbaraAnnKarmanosCancerInstitute,WayneStateUniversitySchoolofMedicine,Detroit,Michigan,UnitedStatesof America,5DepartmentofStructuralandCellularBiology,TulaneUniversitySchoolofMedicine,TulaneCancerCenter,NewOrleans,Louisiana,UnitedStatesofAmerica, 6KeyLaboratoryforMolecularEnzymologyandEngineeringoftheMinistryofEducation,JilinUniversity,Changchun,China,7DepartmentofOncology,WayneState UniversitySchoolofMedicine,Detroit,Michigan,UnitedStatesofAmerica Abstract Background: Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. Histone deacetylase inhibitors(HDACIs)haveshownpromisingantitumoractivitiesagainstpreclinicalmodelsofpancreaticcancer,eitheralone orincombinationwithchemotherapeuticagents.Inthisstudy,wesoughttoidentifyclinicallyrelevanthistonedeacetylases (HDACs)toguidetheselectionofHDACinhibitors(HDACIs)tailoredtothetreatmentofpancreaticcancer. Methodology:HDACexpressioninsevenpancreaticcancercelllinesandnormalhumanpancreaticductalepithelialcells wasdeterminedbyWesternblotting.AntitumorinteractionsbetweenclassI-andclassII-selectiveHDACIsweredetermined byMTTassaysandstandardisobologram/CompuSynsoftwareanalyses.TheeffectsofHDACIsoncelldeath,apoptosisand cellcycleprogression,andhistoneH4,alpha-tubulin,p21,andcH2AXlevelsweredeterminedbycolonyformationassays, flowcytometryanalysis,andWesternblotting,respectively. Results:ThemajorityofclassesIandIIHDACsweredete