The reverse transcriptase encoded by LINE-1 retrotransposons in the genesis, progression and therapy of cancer
Articolo
Data di Pubblicazione:
2016
Abstract:
Inhighereukaryoticgenomes,LongInterspersedNuclearElement1(LINE-1)retrotransposonsrepresentalargefamilyofrepeatedgenomicelements.Theytransposeusingareversetranscriptase(RT),whichtheyencodeaspartoftheORF2pproduct.RTinhibitionincancercells,eitherviaRNAinterference-dependentsilencingofactiveLINE-1elements,orusingRTinhibitorydrugs,reducescancercellproliferation,promotestheirdifferentiationandantagonizestumorprogressioninanimalmodels.Indeed,thenon-nucleosideRTinhibitorefavirenzhasrecentlybeentestedinaphaseIIclinicaltrialwithmetastaticprostatecancerpatients.Anin-depthanalysisofORF2pinamousemodelofbreastcancershowedORF2ptobeprecociouslyexpressedinprecancerouslesionsandhighlyabundantinadvancedcancerstages,whilebeingbarelydetectableinnormalbreasttissue,providingarationaleforthefindingthatRT-expressingtumorsaretherapeuticallysensitivetoRTinhibitors.WesummarizemechanisticandgeneprofilingstudiesindicatingthatabundantLINE-1-derivedRTcan"sequester"RNAsubstratesforreversetranscriptionintumorcells,entailingtheformationofRNA:DNAhybridmoleculesandimpairingtheoverallproductionofregulatorymiRNAs,withaglobalimpactonthecelltranscriptome.Basedonthesedata,LINE-1-ORF2encodedRThasatumor-promotingpotentialthatisexertedatanepigeneticlevel.WeproposeamodelwherebyLINE1-RTdrivesapreviouslyunrecognizedglobalregulatoryprocess,thederegulationofwhichdrivescelltransformationandtumorigenesiswithpossibleimplicationsforcancercell heterogeneity.
Tipologia CRIS:
01.01 Articolo in rivista
Keywords:
LINE-1 retrotransposons; reverse transcriptase; tumorigenesis; differentiation therapy; cancer heterogeneity; epigenetics
Elenco autori:
Spadafora, Corrado
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