| Autor: |
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., Zucman-Rossi, Jessica, Colnot, Sabine, Gougelet, Angélique |
| Zdroj: |
Molecular Therapy; 20240101, Issue: Preprints |
| Abstrakt: |
The CTNNB1gene, encoding β-catenin, is frequently mutated in hepatocellular carcinoma (HCC, ∼30%) and in hepatoblastoma (HB, >80%), in which DLK1/DIO3locus induction is correlated with CTNNB1mutations. Here, we aim to decipher how sustained β-catenin activation regulates DLK1/DIO3locus 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-Wnt responsive element [WRE]) and increasing DLK1/DIO3locus transcription in β-catenin-mutated human HB and mouse models. DLK1-WRE editing by CRISPR-Cas9 approach impaired DLK1/DIO3locus expression and slowed tumor growth in subcutaneous CTNNB1-mutated tumor cell grafts, ApcΔhepHB and β-cateninΔExon3HCC. 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/DIO3locus is an essential determinant of FoxM1-dependent cell proliferation during β-catenin-driven liver tumorigenesis. Targeting the DLK1-WRE enhancer to silence the DLK1/DIO3locus might thus represent an interesting therapeutic strategy to restrict tumor growth in primary liver cancers with CTNNB1mutations. |
| Databáze: |
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