| First Author | Lospinoso Severini L | Year | 2024 |
| Journal | Cell Death Differ | Volume | 31 |
| Issue | 2 | Pages | 170-187 |
| PubMed ID | 38062245 | Mgi Jnum | J:345824 |
| Mgi Id | MGI:7581802 | Doi | 10.1038/s41418-023-01246-6 |
| Citation | Lospinoso Severini L, et al. (2024) SALL4 is a CRL3(REN/KCTD11) substrate that drives Sonic Hedgehog-dependent medulloblastoma. Cell Death Differ 31(2):170-187 |
| abstractText | 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 (CRL3(REN)) and a tumor suppressor lost in ~30% of human SHH-MBs. We demonstrate that CRL3(REN) induces polyubiquitylation and degradation of wild type SALL4, but not of a SALL4 mutant lacking zinc finger cluster 1 domain (DeltaZFC1). 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 CRL3(REN) substrate and a promising therapeutic target in SHH-dependent cancers. |
