SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma

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 similar to 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 (Delta ZFC1). 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.

Automated summary

The Sonic Hedgehog (SHH) pathway plays a crucial role in embryonic development and stemness. The high expression of SALL4, a stemness regulator, is correlated with worse overall survival in patients with SHH-MB. SALL4 interacts with CRL3(REN) and enhances GLI1 transcriptional activity through cooperation with HDAC1. Inhibition of SALL4 suppresses the growth of SHH-MB in mouse models and patient-derived xenograft models, making it a promising therapeutic target.