A circuit involving the lncRNA MB3 and the driver genes MYC and OTX2 inhibits apoptosis in Group 3 Medulloblastoma by regulating the TGF-β pathway via HMGN5

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ABSTRACT Background Group 3 (G3) is one of the most common, aggressive and fatal subtypes of the paediatric cerebellar tumour Medulloblastoma (MB), primarily driven by the MYC oncogene. Targeting MYC has long been challenging and this, combined with our incomplete understanding of G3 MB molecular bases, has hindered the development of effective targeted therapies. Long noncoding RNAs (lncRNAs), with their extensive oncogenic roles, cancer-specific expression, and connection to MYC biology, offer opportunities for unravelling this complexity and providing new insights and therapeutic targets. Methodology Using genome-wide, molecular and cellular assays, we characterised the activity of the MYC-dependent, anti-apoptotic lncRNA lncMB3 in G3 MB cells. Results Through transcriptomic and interactomic analyses, we clarified lncMB3 function and mode-of-action. LncMB3 controls the TGF-β pathway, critically altered in G3 medulloblastomagenesis. This regulation occurs via the direct coding-noncoding RNA interaction between lncMB3 and the mRNA for the epigenetic factor HMGN5, with both sharing targets in the TGF-β cascade. This axis converges on apoptosis through OTX2, another G3 MB driver gene, and photoreceptor lineage genes. Synergistic effects between lncMB3 targeting and cisplatin treatment underscores the relevance of this regulatory network in vitro . Finally, we propose novel ferritin-based nanocarriers as efficient delivery tools for antisense oligonucleotides targeting lncMB3 . Conclusions LncMB3 emerges as a central node linking MYC amplification to apoptosis inhibition through a circuit involving RNA-based mechanisms, G3 MB key drivers and underexplored factors. This integrated framework deepens our understanding of G3 MB molecular underpinnings and lay the foundation for translating lncRNA research into potential applications.

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