4.7 Article

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

Journal

CELL DEATH AND DIFFERENTIATION
Volume -, Issue -, Pages -

Publisher

SPRINGERNATURE
DOI: 10.1038/s41418-023-01246-6

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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.
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.

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