文獻-重點表觀遺傳學(xué)brd4與

提要：葛蘭素公司是世界上最大的制藥公司之一，戴斯?達納克在這家公司帶領(lǐng)一個表這種酶能使甲基附著在組蛋白上，這個過程是包裝的一部分。淋巴瘤是免疫系統(tǒng)的癌癥，大多是由于突變致使EZH2超出了應(yīng)該的范圍，因而使它們所環(huán)繞的沉默，包括所謂的抑癌，而抑癌的任務(wù)是失控的細(xì)胞生長，避免導(dǎo)癥。本文轉(zhuǎn)自 中文 THEbiggestconceptualbreakthroughinthewaroncancerwastherealisationbythe1980sthatitisalwaysageneticdisease.Sometimesthegeneticflawisinherited.Sometimesitistheresultofexposuretoanoutsideagentsuchastobaccosmokeorradioactivity.Sometimesitisplainbadluck;amiscopyingofapieceofDNAduringthenormalprocessofcelldivision.，二十世紀(jì)八十年代，在對癌中實現(xiàn)了最大的概念突破總是一種遺傳性的疾病。遺不過運氣不佳，DNA片斷在正常的細(xì)胞過程中進行了錯誤的。，Turningthatbreakthroughintomedicine,though,ishard.NoonehasworkedouthowtorepairDNAdirectly.Itis,rather,aquestionofdiscoveringthebiochemicalconsequencesofthegeneticdamageandtryingtodealwiththoseinstead.Butrecently,anotherpatternhasemerged.Itistooearlytocallitabreakthroughassignificantasthecancer-is-caused-by-broken-genesfinding,butitmight是遺傳損傷的生化，并試圖處理這些改變。但最近，又出現(xiàn)了另一種模式。把它稱為重大突破還言之尚早，它的重大意義還趕不上是由破碎造成的這一發(fā)現(xiàn)，但它有Thepatterninquestionisthatmanyofthegeneswhosebreakageleadstocancerarethemselvesinvolvedinaspecificsortofgeneticregulation,knownasepigenetics.ThisswitchesgenesonandoffbyplasteringeithertheirDNAortheandacetylgroups.Thenatureofthesereactionsmeansepigeneticprocessesaresusceptibletochemicalinterventioninawaythatgeneticmutationsarenot.Theyare,inotherwords,opentodrugtreatment.Andthatiswhyepigeneticswasthesubjectofaparticularlyinterestingsession,heldonApril1st,atameetingoftheAmericanAssociationforCancerResearchinChicago. 學(xué)這一模式通過用甲基和乙?；哟赝磕ㄆ銬NA或支撐 中DNA的蛋白質(zhì)開關(guān) 遺傳學(xué)會成為4月1日召開的一次特別有趣的例會的 Aproblemofoverregulation過 的問DashDhanak,wholeadstheepigeneticsresearchgroupatGlaxoSmithKline,oneoftheworld’sbiggestdrugcompanies,describedtothemeetinghiseffortstodevelopasubstancethatwillinhibittheactivityofanenzymecalledEZH2.Thisenzymeattachesmethylgroupstohistoneproteins,whicharepartofthechromosomalpackaging.Alotoflymphomas—cancersoftheimmunesystem—arecausedbymutationsthatmakeEZH2overactive.Suchoveractivitymethylateshistonesmorethantheyshouldbeandthussilencesthegenestheysurround,includingso-calledtumour-suppressorgeneswhosejobistostoptheuncontrolledcellgrowththatcauses葛蘭素公司是世界上最大的制藥公司之一，戴斯?達納克在這家公司帶領(lǐng)一個表觀遺傳能使甲基附著在組蛋白上，這個過程是包裝的一部分。淋巴瘤是免疫系統(tǒng)的，大多是由于突變致使EZH2應(yīng)該的范圍，因而使它們所環(huán)繞的沉默，包括所謂的抑癌，而抑癌的任務(wù)是阻止失控的細(xì)胞生長，避免導(dǎo)癥。WhenDrDhanakandhiscolleaguestreatedlymphomacellswithanewlydevelopedinhibitor,currentlyreferredtobytheunmemorablenameGSK,theyfoundthatbothcellculturesandlaboratoryanimalswithGSK,theyfounditalsoreducestheproliferationoftumourcellswhile,crucially,havingnoapparenteffectonnearbynormalcells.目前有種新開發(fā)的抑制劑叫GSK JamesBradneroftheDana-FarberCancerInstitute,inBoston,describedasecondepigeneticapproachtotreatingcancer.HisgrouphaveshownthatasubstanceknownasJQ1,whichinhibitsanepigeneticregulatorcalledBRD4,blockstheactivityofisinvolvedintheexpressionofabout15%ofhumangenes.Notsurprisingly,then,whenitgoeswrongitisoneofthemostcommoncausesofcancer. 的性。MycDNA15％的人類表達。當(dāng)它出錯時就成了最常見的原因Despitenumerousattempts,researchershavebeenunabletofindawaytoblocktheactivityofMycdirectly.DrBradner,however,reasonedthatblockingBRD4,whichisoneofMyc’scollaborators,mightdothejobindirectly.TotestthisthoughtheandhiscolleaguestreatedmicesufferingfromMyc-drivenmyelomawithJQ1.Anditworked.JQ1,theyfound,shutdownMyc-activatedgenesandslowedtheproliferationofmyelomacells. 式來直接阻斷Myc 的協(xié)作者之一BRD4可能會間接阻斷其活性。為了測試這個想法他和他的同事用JQ1處理患有Myc JQ1關(guān)閉了激活Myc的 AlthoughneitherGSKnorJQ1isreadyforhumantrials,twoothersortsofepigeneticdrugsarealreadyonthemarket.DNA-demethylatingagents,intheformofazacitidine,soldasVidazabyCelgene,ofSummit,NewJersey,anddecitabine,soldasDacogenbyEisai,aJapanesecompany,areusedtotreatmyelodysplasticsyndromes,theprecursorsofacutemyelogenousleukaemia.Andhistone-deacetylaseinhibitors,madebyCelgeneandbyMerck,anotherNewJersey-basedfirm,arebeingusedtotreatarareillnesscalledcutaneousT-celllymphoma.GSKJQ1都沒做好進行試驗的準(zhǔn)備，但有另外兩種表觀遺傳藥物已經(jīng)上市了。DNA去甲基劑以阿扎胞苷的形式由新澤西州沙米特市Celgene公司用Vidaza為商品名銷售，丁西他濱由EisaiDacogenTMorerecently,researchersledbyStephenBaylinatJohnsHopkinsSchoolofMedicine,azacitidineslowedtumourgrowthinsomepeoplewithadvancedlungcancer.Thisdeployedsuccessfullyagainstasolidtumour,ratherthanaleukaemiaoralymphoma(solidtumoursarehardertotreat,becausethedrughastopenetratethem).And,second,someoftheparticipantsinDrBaylin’sstudywhodidnotshowmuchresponsetothetrialitselfthenwentontoshowanunexpectedlygoodreactiontotheroutinechemotherapeuticdrugswhichwereemployedonthemnext.Althoughitistooearlytosayforsure,DrBaylinspeculatesthathisepigeneticdrugsalteredthetumour Thatisquitepossible.Unlikeotherformsofgeneregulation(thoseinvolvingtranscriptionfactors,forexample),epigeneticchangesarepassedonduringcelldivisiontodaughterandgranddaughtercellsuntiltheyareactivelyerased.Onceerased,though,theydonotr