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1、PublishedOnlineFirstMay30,2013;DOI:10.1158/0008-5472.CAN-12-3165CancerMolecularandCellularPathobiologyResearchHistoneDemethylaseRBP2PromotesLungTumorigenesisandCancerMetastasis1,411221Yu-ChingTeng,Cheng-FengLee,Ying-ShiuanLi,Yi-RenChen,Pei-WenHsiao,Meng-YuChan,771518Feng-MaoLin,Hsien-DaHu
2、ang,Yen-TingChen,Yung-MingJeng,Chih-HungHsu,QinYan,1,3,4,61,4Ming-DawTsai,andLi-JungJuanAbstractTheretinoblastomabindingproteinRBP2(KDM5A)isahistonedemethylasethatpromotesgastriccancercellgrowthandisenrichedindrug-resistantlungcancercells.Intumor-pronemicelackingthetumorsuppressorgeneRBor
3、MEN1,geneticablationofRBP2cansuppresstumorinitiation,butthepathogenicbreadthandmechanisticaspectsofthiseffectrelativetohumantumorshavenotbeendefined.Here,weapproachedthisquestioninthecontextoflungcancer.RBP2wasoverexpressedinhumanlungcancertissueswhereitsdepletionimpairedcellproliferation,
4、motility,migration,invasion,andmetastasis.RBP2oncogenicityreliedonitsdemethylaseandDNA-bindingactivities.RBP2upregulatedexpressionofcyclinsD1andE1whilesuppressingtheexpressionofcyclin-dependentkinaseinhibitorp27(CDKN1B),eachcontributingtoRBP2-mediatedcellproliferation.Expressionmicroarray
5、analysesrevealedthatRBP2promotedexpressionofintegrin-b1(ITGB1),whichisimplicatedinlungcancermetastasis.MechanisticinvestigationsestablishedthatRBP2bounddirectlytothep27,cyclinD1,andITGB1promotersandthatexogenousexpressionofcyclinD1,cyclinE1,orITGB1wassufficienttorescueproliferationormigrat
6、ion/invasion,respectively.Takentogether,ourresultsestablishanoncogenicroleforRBP2inlungtumorigenesisandprogressionanduncovernovelRBP2targetsmediatingthisrole.CancerRes;73(15);4711–21.Ó2013AACR.IntroductioningonitsJmjCdomain(8,9).Therefore,RBP2isalsocalledKDM5AorJARID1A.ThehumanJARID1prote
7、infamilycon-Retinoblastomabindingprotein-2(RBP2)wasoriginallysistsoffourmembersincludingRBP2/JARID1A,PLU1/JAR-identifiedasaretinoblastomaprotein(Rb)-bindingpartnerID1B,SMCX/JARID1C,andSMCY/JARID1D(10).Thesefour(1).Subsequently,itwasshowntoparticipateintranscriptionpr
