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DLK1/DIO3 locus upregulation by a β-catenin-dependent enhancer drives cell proliferation and liver tumorigenesis

dc.rights.licenseopenen_US
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorSANCEAU, Julie
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorPOUPEL, Lucie
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorJOUBEL, Camille
hal.structure.identifierInstitut Cochin [IC UM3 (UMR 8104 / U1016)]
dc.contributor.authorLAGOUTTE, Isabelle
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorCARUSO, Stefano
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorPINTO, Sandra
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorDESBOIS-MOUTHON, Christèle
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorGODARD, Cécile
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorHAMIMI, Akila
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorMONTMORY, Enzo
hal.structure.identifierInstitut de Génomique d'Evry [IG]
dc.contributor.authorDULARY, Cécile
hal.structure.identifierInstitut de Génomique d'Evry [IG]
dc.contributor.authorCHANTALAT, Sophie
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorROEHRIG, Amélie
hal.structure.identifierInstitut de Génomique d'Evry [IG]
dc.contributor.authorMURET, Kevin
hal.structure.identifierInstitut Cochin [IC UM3 (UMR 8104 / U1016)]
dc.contributor.authorSAINT-PIERRE, Benjamin
hal.structure.identifierInstitut de Génomique d'Evry [IG]
dc.contributor.authorDELEUZE, Jean-François
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorMOUILLET-RICHARD, Sophie
hal.structure.identifierInstitut de Génétique Moléculaire de Montpellier [IGMM]
dc.contributor.authorFORNÉ, Thierry
hal.structure.identifierBiothérapies des maladies génétiques et cancers
hal.structure.identifierBoRdeaux Institute in onCology [Inserm U1312 - BRIC]
dc.contributor.authorGROSSET, Christophe F.
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorCOLNOT, Sabine
hal.structure.identifierCentre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
dc.contributor.authorGOUGELET, Angélique
dc.date.accessioned2025-06-13T08:33:28Z
dc.date.available2025-06-13T08:33:28Z
dc.date.issued2024-02-03
dc.identifier.issn1525-0016en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/206898
dc.description.abstractEnThe CTNNB1 gene, encoding β-catenin, is frequently mutated in hepatocellular carcinoma (HCC, ∼30%) and in hepatoblastoma (HB, >80%), in which DLK1/DIO3 locus induction is correlated with CTNNB1 mutations. Here, we aim to decipher how sustained β-catenin activation regulates DLK1/DIO3 locus expression and the role this locus plays in HB and HCC development in mouse models deleted for Apc (ApcΔhep) or Ctnnb1-exon 3 (β-cateninΔExon3) and in human CTNNB1-mutated hepatic cancer cells. We identified an enhancer site bound by TCF-4/β-catenin complexes in an open conformation upon sustained β-catenin activation (DLK1-WRE) and increasing DLK1/DIO3 locus transcription in β-catenin-mutated human HB and mouse models. DLK1-WRE editing by CRISPR/Cas9 approach impaired DLK1/DIO3 locus expression and slowed tumor growth in subcutaneous CTNNB1-mutated tumor cell grafts, ApcΔhep HB and β-cateninΔExon3 HCC. Tumor growth inhibition resulted either from increased FADD expression and subsequent caspase-3 cleavage in the first case, or from decreased expression of cell cycle actors regulated by FoxM1 in the others. Therefore, the DLK1/DIO3 locus is an essential determinant of FoxM1-dependent cell proliferation during β-catenin-driven liver tumorigenesis. Targeting the DLK1-WRE enhancer to silence the DLK1/DIO3 locus might thus represent an interesting therapeutic strategy to restrict tumor growth in primary liver cancers with CTNNB1 mutations.
dc.language.isoENen_US
dc.subject.enprimary liver cancers
dc.subject.entransgenic mice
dc.subject.enin vivo CRISPR/Cas9
dc.subject.enβ-catenin
dc.subject.enenhancer site
dc.subject.ennon-coding RNAs
dc.subject.entargeted therapies
dc.title.enDLK1/DIO3 locus upregulation by a β-catenin-dependent enhancer drives cell proliferation and liver tumorigenesis
dc.typeArticle de revueen_US
dc.identifier.doi10.1016/j.ymthe.2024.01.036en_US
dc.subject.halSciences du Vivant [q-bio]en_US
bordeaux.journalMolecular Therapyen_US
bordeaux.hal.laboratoriesBRIC (Bordeaux of Institute of Oncology) - U1312en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcehal
hal.identifierhal-04441676
hal.version1
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exportfalse
workflow.import.sourcehal
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Molecular%20Therapy&rft.date=2024-02-03&rft.eissn=1525-0016&rft.issn=1525-0016&rft.au=SANCEAU,%20Julie&POUPEL,%20Lucie&JOUBEL,%20Camille&LAGOUTTE,%20Isabelle&CARUSO,%20Stefano&rft.genre=article


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