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SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma.
Lospinoso Severini, Ludovica; Loricchio, Elena; Navacci, Shirin; Basili, Irene; Alfonsi, Romina; Bernardi, Flavia; Moretti, Marta; Conenna, Marilisa; Cucinotta, Antonino; Coni, Sonia; Petroni, Marialaura; De Smaele, Enrico; Giannini, Giuseppe; Maroder, Marella; Canettieri, Gianluca; Mastronuzzi, Angela; Guardavaccaro, Daniele; Ayrault, Olivier; Infante, Paola; Bufalieri, Francesca; Di Marcotullio, Lucia.
Affiliation
  • Lospinoso Severini L; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Loricchio E; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Navacci S; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Basili I; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Alfonsi R; Institut Curie, PSL Research University, CNRS UMR, INSERM, 91401, Orsay, France.
  • Bernardi F; Centro Nazionale per il Controllo e la Valutazione dei Farmaci, Istituto Superiore di Sanità, 00161, Rome, Italy.
  • Moretti M; Institut Curie, PSL Research University, CNRS UMR, INSERM, 91401, Orsay, France.
  • Conenna M; Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U, 91401, Orsay, France.
  • Cucinotta A; Department of Experimental Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Coni S; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Petroni M; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • De Smaele E; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Giannini G; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Maroder M; Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza, 00161, Rome, Italy.
  • Canettieri G; Department of Experimental Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Mastronuzzi A; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Guardavaccaro D; Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza, 00161, Rome, Italy.
  • Ayrault O; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Infante P; Department of Molecular Medicine, University of Rome La Sapienza, 00161, Rome, Italy.
  • Bufalieri F; Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza, 00161, Rome, Italy.
  • Di Marcotullio L; Department of Pediatric Haematology and Oncology, and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, 00165, Rome, Italy.
Cell Death Differ ; 31(2): 170-187, 2024 02.
Article in En | MEDLINE | ID: mdl-38062245
ABSTRACT
The Sonic Hedgehog (SHH) pathway is crucial regulator of embryonic development and stemness. Its alteration leads to medulloblastoma (MB), the most common malignant pediatric brain tumor. The SHH-MB subgroup is the best genetically characterized, however the molecular mechanisms responsible for its pathogenesis are not fully understood and therapeutic benefits are still limited. Here, we show that the pro-oncogenic stemness regulator Spalt-like transcriptional factor 4 (SALL4) is re-expressed in mouse SHH-MB models, and its high levels correlate with worse overall survival in SHH-MB patients. Proteomic analysis revealed that SALL4 interacts with REN/KCTD11 (here REN), a substrate receptor subunit of the Cullin3-RING ubiquitin ligase complex (CRL3REN) and a tumor suppressor lost in ~30% of human SHH-MBs. We demonstrate that CRL3REN induces polyubiquitylation and degradation of wild type SALL4, but not of a SALL4 mutant lacking zinc finger cluster 1 domain (ΔZFC1). Interestingly, SALL4 binds GLI1 and cooperates with HDAC1 to potentiate GLI1 deacetylation and transcriptional activity. Notably, inhibition of SALL4 suppresses SHH-MB growth both in murine and patient-derived xenograft models. Our findings identify SALL4 as a CRL3REN substrate and a promising therapeutic target in SHH-dependent cancers.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Neoplasms / Cerebellar Neoplasms / Medulloblastoma Limits: Animals / Humans Language: En Journal: Cell Death Differ Year: 2024 Document type: Article Affiliation country:
Fulltext
Add to My VHL
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PubMed Links
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Neoplasms / Cerebellar Neoplasms / Medulloblastoma Limits: Animals / Humans Language: En Journal: Cell Death Differ Year: 2024 Document type: Article Affiliation country: