DLK1/DIO3 locus upregulation by a β-catenin-dependent enhancer drives cell proliferation and liver tumorigenesis
In: ISSN: 1525-0016, 2024
Online
academicJournal
Zugriff:
International audience ; The 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.
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DLK1/DIO3 locus upregulation by a β-catenin-dependent enhancer drives cell proliferation and liver tumorigenesis
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Autor/in / Beteiligte Person: | Sanceau, Julie ; Poupel, Lucie ; Joubel, Camille ; Lagoutte, Isabelle ; Caruso, Stefano ; Pinto, Sandra ; Desbois-Mouthon, Christèle ; Godard, Cécile ; Hamimi, Akila ; Montmory, Enzo ; Dulary, Cécile ; Chantalat, Sophie ; Roehrig, Amélie ; Muret, Kevin ; Saint-Pierre, Benjamin ; Deleuze, Jean-François ; Mouillet-Richard, Sophie ; Forné, Thierry ; Grosset, Christophe F. ; Colnot, Sabine ; Gougelet, Angélique ; Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)) ; École Pratique des Hautes Études (EPHE) ; Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité) ; Institut Cochin (IC UM3 (UMR 8104 / U1016)) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité) ; Institut de Génomique d'Evry (IG) ; Université Paris-Saclay-Institut de Biologie François JACOB (JACOB) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) ; Institut de Génétique Moléculaire de Montpellier (IGMM) ; Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM) ; Biothérapies des maladies génétiques et cancers ; Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM) ; BoRdeaux Institute in onCology (Inserm U1312 - BRIC) ; Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
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Zeitschrift: | ISSN: 1525-0016, 2024 |
Veröffentlichung: | HAL CCSD ; Cell Press, 2024 |
Medientyp: | academicJournal |
DOI: | 10.1016/j.ymthe.2024.01.036 |
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