7,7”-dimethoxyagastisflavone induced MYCN/MYBL2-dependent apoptosis and metabolism reprogramming in Sonic Hedgehog medulloblastoma

Background: Medulloblastoma (MB) is the most common malignant pediatric brain cancer. Patients diagnosed with Sonic Hedgehog (SHH) MB typically exhibit highly metastatic tumors and have an unfavorable prognosis. 7,7”-Dimethoxyagastisflavone (DMGF), a biflavonoid compound, isolated from needles of Taxus x media cv. Hicksii. The purpose of this study is to explore the potential targets of SHH MB and the therapeutic effects of DMGF in SHH MB. Methods: RNA sequencing was used to analyze malignancy-related genes in SHH MB patient tumors. Experiments on cytotoxicity, apoptosis, cell cycle, migration, F-actin assembly, EMT, metabolite changes, and macrophage polarization demonstrated that DMGF induced cell death by inhibiting MYCN and MYBL2. The therapeutic effect of DMGF was studied in MB orthotopic xenograft mice. Three-dimensional images exhibited the brain-wide distribution of MB tumors. Patient-derived MB cells were utilized to demonstrate the potential of DMGF as a future therapy. Results: Taiwanese SHH MB patients with high MYCN and MYBL2 expression had lower 5-year overall survival, suggesting that MYCN and MYBL2 are related to the malignancy. DMGF decreased MYCN and MYBL2 expression, which arrests the cell cycle, induces apoptosis, impedes cell migration, and inhibits the EMT response. DMGF disrupted redox balance and inhibited energy-related metabolism in SHH MB cells. DMGF-induced macrophage polarization that built an antitumor microenvironment. The inhibitory effects of DMGF on MYCN/MYBL2 were also confirmed in patient-derived MB cells. Conclusion: Inhibiting MYCN and MYBL2 is the key to DMGF’s anti-tumor effects. These findings suggest the potential of DMGF as a future chemotherapeutic agent for MB treatment.