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.

SALL4 is a CRL3^REN/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. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - (2023). [10.1038/s41418-023-01246-6]

SALL4 is a CRL3^REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma

Ludovica Lospinoso Severini
Primo
;
Elena Loricchio;Shirin Navacci;Irene Basili;Romina Alfonsi;Marta Moretti;Marilisa Conenna;Antonino Cucinotta;Sonia Coni;Marialaura Petroni;Enrico De Smaele;Giuseppe Giannini;Marella Maroder;Gianluca Canettieri;Angela Mastronuzzi;Paola Infante;Francesca Bufalieri;Lucia Di Marcotullio
2023

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.
2023
medulloblastoma; hedgehog pathway; sall4; ren/kctd11; ubiquitylation; cancer therapy
01 Pubblicazione su rivista::01a Articolo in rivista
SALL4 is a CRL3^REN/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. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - (2023). [10.1038/s41418-023-01246-6]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1692856
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