H3K27andH3K4AlterationsinBladderCancerWhyKDM6A/UtxMutationsinHumanBladderCancer?KDM6A/UtxMutationsHumanBladderCancer?OverviewofKDM6APhylogeneticTreeoftheJmjCFamilyofDemethylasesKloseetal.NatureReviewsGenetics7,715–727(September2006)|doi:10.1038/nrg1945KDM6A/UTXSpecificallyDemethylatesHistoneH3K27InVitroPublishedbyAAASDemethylases/methyltransferasesinTranscriptionalRegulationofDevelopmentalGenesH3K27MethylationRegulatesExpressionofSeveralHOXGeneFamilyMembersAhistoneH3lysine27demethylaseregulatesanimalposteriordevelopmentFeiLan,PeterE.Bayliss,JohnL.Rinn,JohnathanR.Whetstine,JordonK.Wang,ShuzhenChen,ShigekiIwase,RomanAlpatov,IrinaIssaeva,EliCanaani,ThomasM.Roberts,HowardY.Chang&YangShiNature449,689-694(11October2007)doi:10.1038/nature06192SomaticmutationsofthehistoneH3K27demethylasegeneUTXinhumancancerGijsvanHaaften,GillianLDalgliesh,HelenDavies,etal.NatureGenetics41,521-523(2009)Publishedonline:29March2009KDM6ADeletionsandMyeloma:2009ASHAbstractsKDM6ADeletionsandBladdercancer:2010ASHAbstractTheFlipside:H3K27Methyltransferase,EZH2EZH2andcancerInallcases,occurrenceofthemutantEZH2genewasheterozygous.AllofthemutantformscouldbeincorporatedintoPRC2complex.PRC2complexwithmutantEZH2proteinshadreducedenzymeactivityinvitro(onunmethylatedhistonepeptides).DeregulationofH3K27methylationincancerEvaMartinez-Garcia&JonathanDLichtJournalname:NatureGeneticsVolume:42,Pages:100–101Yearpublished:(2010)DOI:EZH2mRNAlevelwasdirectlycorrelatedwithcellularproliferationinprimarygerminalcenterdiffuselargeB-celllymphomatumors.ExpressionlevelsofEZH2andthePRC1componentBMI1havebothbeenlinkedtolymphomagenesisandthedegreeofmalignancyofB-cellnon-Hodgkinslymphomas.siRNA-mediateddown-regulationofEZH2inDLBCLcellsresultedinacutecellcyclearrestattheG(1)/Stransitionandup-regulationoftumorsuppressortargetgenes(Velichutinaetal.Blood.2010Dec9;116(24):5247-55).LedtofurtherstudiesoftheenzymologyofEZH2Tyr641mutants…Y641-mutantEZH2PreferentiallyCatalyzesDi-andTrimethylationofHistoneH3K27Enzym