LSD1及与肿瘤关系研究进展

2010199ChinaCancer,2010,Vol.19,No.9LSD1，（，310014）ResearchProgressinRelationshipBetweenLSD1andTumorMAYing-Yu,TAOHou-Quan：1(LSD1)FAD，H3K4H3K9。，LSD1，。LSD1,、，。：LSD1；；：R730.1：A：1004-0242（2010）09-0599-05，，，。2004，(lysinespecificdemethylase1，LSD1)，[1]。LSD1，[2,3]，LSD1，[4]。LSD1，。1LSD1，H2A、H2B，H3、H4，H2A、H2BH3、H4，DNA。，、、、。6（H3K4、H3K9、H3K27、H3K36、H3K79H4K20），H3K4、H3K36H3K79[5]。LSD1KIAA0601，p110b，BHC110，NPAO，[6~10]。LSD1NSWIRM（Swi3p、Rsc8pandMoira），Tower，CFAD[1,11]。SWIRM[12]，TowerC，，FAD，TowerLSD1[13]。LSD1(me1)(me2)，H3K4，，LSD1H3K9[3]。，LSD1，CoREST、BHC80、HDAC1/2、BRAF，LSD1[7,14]。LSD1H3K4Me，，LSD1CoREST，CoRESTLSD1，LSD1[15,16]。BHC80LSD1LSD1[16]；LSD1：2010-04-01；：2010-06-18：Email:[e-mail]5992010199ChinaCancer,2010,Vol.19,No.9H3K4H3K9[17]，H3K4，，H3K9。LSD1p53，370(K370Me)(K370Me2)p53，p53p53[18]；Wang[19]，LSD1DNADnmt1Dnmt1，DNA。2LSD12.1LSD1，（androgenreceptor，AR），。，，。，。Metzger[20]LSD1，[5]，。，，LSD1AR[3,21]，LSD1。Seligson[22]，Kahl[21]，LSD1，。2.2LSD1，LSD1，[4,21,23,24]，。，LSD1[24]。Wang（Mi-2/nucleosomeremodelinganddeacetylase，NuRD）ATP，，。ChIP-DSL、Real-TimePCR、Westernblot，LSD1/NuRD—，β1（TGF-β1），LSD1TGF-β1。-，LSD1。LSD1，LSD1，[25]。LSD1，LSD1，LSD1。Kwon[26]578，58%LSD1，MCF7，LSD1α，[2]。Lim[27]LSD1（ER），LSD1，siRNALSD1，LSD1。Saramaki[28]MDA-MB453，D1α，25-D3D（vitaminDresponseelement，VDRE）p21（transcriptionstartsite，TSS)，p21mRNA。，D（vi-taminDreceptor，VDR）VDRERNA（phosphorylatedRNApolymerase，p-Pol）TSSVDRETSS，LSD16002010199ChinaCancer,2010,Vol.19,No.9CBP。siRNALSD1。1α，25-D3p21。2.3LSD1，。，DNA[29~31]。LSD1[3]Co-Rest[16]，Rest，LSD1。LSD1H3K4H3K9，。Schulte[32]，LSD1，，LSD1。Wang，，LSD1。siRNALSD1，，，H3K4；，LSD1，H3K4，，LSD1，，[32]。2.4LSD1Hayami[34]LSD1，cDNALSD1，SiRNALSD1。LSD1，LSD1。LSD1[35,36]，。TAL1，T，E2A/HEB，[37]。，LSD1TAL1TAL1LSD1TAL1E2A/HEB，[38]。，，LSD1[39]，LSD1。LSD1SFRP，LSD1DNASFRP2，[40]。hTERT，90%，，Zhu[41]，LSD1，H3K4hTERT，(histonedeacetylases,HDACs)，hTERT，。3LSD1，。，，。，，，。LSD1，。Kahl[21]，LSD1，Wang[25]LSD1，LSD1。LSD1，；，LSD1，。6012010199ChinaCancer,2010,Vol.19,No.9：[1]ShiY,LanF,MatsonC,etal.His-tonedemethylationmediatedbythenu-clearamineoxidasehomologLSD1[J].Cell,2004,119(7):941-953.[2]Garcia-BassetsI,KwonYS,TeleseF,etal.Histonemethylation-dependentmechanismsimposeliganddependencyforgeneactivationbynuclearreceptors[J].Cell,2007,128(3):505-518.[3]MetzgerE,WissmannM,YinN,etal.LSD1demethylatesrepressivehistonemarkstopromoteandrogen-receptor-de-pendenttranscription[J].Nature,2005,437(7057):436-439.[4]WangGG,AllisCD,ChiP.Chro-matinremodelingandcancer,partI:Co-valenthistonemodifications[J].TrendsMolMed,2007,13(9):363-372.[5]MartinC,ZhangY.Thediversefunctionsofhistonelysinemethylation[J].NatRevMolCellBiol,2005,6(11):838-849.[6]HakimiMA,DongY,LaneWS,etal.AcandidateX-linkedmentalretardationgeneisacomponentofanewfamilyofhistonedeacetylase-containingcomplexes[J].JBiolChem,2003,278(9):7234-7239.[7]HumphreyGW,WangY,RussanovaVR,etal.StablehistonedeacetylasecomplexesdistinguishedbythepresenceofSANTdomainproteinsCoREST/ki-aa0071andMta-L1[J].JBiolChem,2001,276(9):6817-6824.[8]ShiY,SawadaJ,SuiG,etal.Coor-dinatedhistonemodificationsmediatedbyaCtBPco-repressorcomplex[J].Na-ture,2003,422(6933):735-738.[9]TongJK,HassigCA,SchnitzlerGR,etal.ChromatindeacetylationbyanATP-dependentnucleosomeremodellingcomplex[J].Nature,1998,395(6705):917-921.[10]YouA,TongJK,GrozingerCM,etal.CoRESTisanintegralcomponentoftheCoREST-humanhistonedeacetylasecomplex[J].ProcNatlAcadSci,2001,98(4):1454-1458.[11]LanF,NottkeAC,ShiY.Mecha-nismsinvolvedintheregulationofhis-tonelysinedemethylases[J].CurrOpinCellBiol,2008,20(3):316-325.[12]AravindL,IyerLM.TheSWIRMdomain:aconservedmodulefoundinchromosomalproteinspointstonovelchromatin-modifyingactivities[J].GenomeBiol,2002,3(8):RE-SEARCH0039.[13]StavropoulosP,BlobelG,HoelzA.Crystalstructureandmechanismofhu-manlysine-specificdemethylase-1[J].NatStructMolBiol,2006,13(7):626-632.[14]LeeMG,WynderC,CoochN,ShiekhattarR.AnessentialroleforCoR-ESTinnucleosomalhistone3lysine4demethylation[J].Nature,2005,437(7057):432-435.[15]LeeMG,WynderC,BocharDA,etal.Functionalinterplaybetweenhistonedemethylaseanddeacetylaseenzymes[J].MolCellBiol,2006,26(17):6395-6402.[16]ShiYJ,MatsonC,LanF,etal.RegulationofLSD1histonedemethylaseactivitybyitsassociatedfactors[J].MolCell,2005,19(6):857-864.[17]WysockaJ,MilneTA,AllisCD.TakingLSD1toanewhigh[J].Cell,2005,122(5):654-658.[18]HuangJ,SenguptaR,EspejoAB,etal.p53isregulatedbythelysinedemethylaseLSD1[J].Nature,2007,449(7158):105-108.[19]WangJ,HeviS,KurashJK,etal.ThelysinedemethylaseLSD1(KDM1)isrequiredformaintenanceofglobalDNAmethylation[J].NatGenet,2009,41(1):125-129.[20]MullerJM,MetzgerE,GreschikH,etal.ThetranscriptionalcoactivatorFHL2transmitsRhosignalsfromthecellmembraneintothenucleus[J].EmboJ,2002,21(4):736-748.[21]KahlP,GullottiL,HeukampLC,etal.Androgenreceptorcoactivatorsly-sine-specifichistonedemethylase1andfourandahalfLIMdomainprotein2predictriskofprostatecancerrecurrence[J].CancerRes,2006,66(23):11341-11347.[22]SeligsonDB,HorvathS,ShiT,etal.Globalhistonemodificationpatternspre-dictriskofprostatecancerrecurrence[J].Nature,2005,435(7046):1262-1266.[23]FornerisF,Bind