Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with a 5-year survival rate of 75-80%. Despite advances in standard-of-care therapies, significant long-term neuroendocrine and neurocognitive side effects underscore the urgent need for more effective, less toxic treatments. Through comprehensive analysis of human MB datasets, we identified Ras-responsive element binding protein 1 (RREB1) as a transcription factor significantly overexpressed in Group 3 (G3) and Group 4 (G4) tumors. Functional studies demonstrated that RREB1 is essential for the proliferation of G3 MB cell lines and patient-derived xenografts, with its knockdown significantly impairing cell growth. To understand the molecular mechanisms underlying RREB1’s oncogenic role, we performed RNA sequencing on RREB1-depleted cells to identify RREB1-regulated genes and CUT&RUN to identify RREB1 binding sites. Integration of these datasets revealed several TGF-β target genes (E2F5, ID1, INHBE, and GREM2) as direct transcriptional targets of RREB1, suggesting a regulatory role for RREB1 in TGF-β signaling. Furthermore, high-throughput drug screening identified a MET inhibitor that effectively downregulates RREB1 protein levels and inhibits proliferation in vitro. Ongoing studies aim to validate the therapeutic efficacy of MET inhibition in vivo. Together, these findings establish RREB1 as a critical regulator of G3 MB and highlight the potential of MET inhibitors as a novel therapeutic strategy to target this pathway. Future work will explore the broader implications of RREB1 regulation in MB and the therapeutic potential of combining MET inhibition with existing therapies.
Masihi et al. (2025) studied this question.