Sirt1 sustains Sonic hedgehog signaling to promote medulloblastoma progression through regulating Gli3 processing.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor with poor prognosis, high recurrence, and severe treatment-related toxicities. One-third of MB are driven by aberrant activation of the Sonic hedgehog (SHH) signaling pathway. In current study, through analysis of clinical patient cohorts and animal model database, and utilizing genetically engineered primary and xenograft mouse MB models, we investigated the role of Sirtuin1 (Sirt1), a class III histone deacetylase (HDAC), in SHH signaling and MB. We found that Sirt1 was highly expressed in both human and mouse SHH-type MB, and its expression positively correlated with SHH pathway activity and tumor proliferation. Knockdown of Sirt1 in primary MB cells significantly suppressed SHH signaling and MB proliferation in vitro, further impaired neoplastic progression and extended survival in orthotopic transplantation MB model. Mechanistically, we discovered that Sirt1 modulates SHH signaling at downstream by interacting with and deacetylating full-length Gli3 (Gli3FL), thereby inhibiting its proteolytic processing into the repressor form (Gli3R), which attenuates the negative feedback regulation of SHH signaling, sustaining pathway activation and promoting tumor progression. Importantly, pharmacological inhibition of Sirt1 demonstrated promising therapeutic efficacy in both subcutaneous transplantation and primary MB models. Our findings identify Sirt1 as a potential therapeutic target for SHH-driven MB and other cancers.