Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Targeting Group3 Medulloblastoma by the anti-PRUNE-1 and anti-LSD1- KDM1A molecules augments their potential therapeutic value.

ABSTRACT: The combination of AA7.1 and SP2577 affects neuronal commitment,leukocyte differentiation and mitochondrial metabolism. To better dissect the mechanisms of action of these two drugs and to investigate the genes and pathways affected we treated primary Group3 MB for 24 hours with 100μM AA7.1 (pruneinhibotor) , 22.5μM SP2577 ( LSD1 inhibitor) and the combination and we performed RNA-Seq. Vehicle treated cells were used as control. Gene expression analysis showed up-regulation of genes implicated in neuronal differentiation, mitochondrial metabolism in cells treated with Prune-1 and LSD1 inhibitors, with stronger evidence in cells treated with the combination of two drugs.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo sapiens

SUBMITTER: Massimo Zollo

PROVIDER: E-MTAB-13616 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Medulloblastoma (MB) is the most common malignant brain tumor. MB is a cerebellar tumor that occurs mostly in children between the ages of 3-7 years but also in adults. Human MBs are classified into four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which with distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs characterized by C-MYC (MYC) overexpression in ~17% of cases from gene amplification with stem like properties, are the most aggressive and least curable with current therapeutic regimen. Using an orthotopic transplant approach, we found that enforced expression of MYCN in cerebellar granule neural progenitors (CGNPs) from 5-7 days old Trp53-null mice induced SHH MBs after transfer in the cortices or cerebella of naive recipient mice. In contrast, overexpression of MYC induced G3 MBs. Because MYCN and MYC bind to the same E-box DNA sequences, we hypothesized that the difference between MYC and MYCN-induced gene expression and tumor identity might be due to their interaction with different partners in CGNPs. In this study, we investigated the role of the Myc interacting zinc finger protein 1 (MIZ1). We found that MIZ1 binds with higher affinity to MYC than to MYCN and that MIZ1 and MYC co-occupy thousands of promoters in G3 MB. Remarkably, enforced expression of a MYC mutant (MYCV394D) that no longer binds to MIZ1 in Trp53-null CGNPs or expression of wild type MYC in CGNPs that lack functional Miz1 resulted in massive changes of the resulting tumorâ??s transcriptional program. Tumors differed from both SHH and G3 medulloblastoma and had a later time of onset compared to MYC-driven G3 medulloblastoma. Our data demonstrate that interaction of MYC with MIZ1 is required for the development of G3 medulloblastoma. ChIP-Seq experiments for Miz1, c-Myc and NMyc from murine medulloblastoma material. Either sorted tumor cells (Miz1 and c-Myc) or spheres from tumor cells (Miz1 and NMyc) were used. Input-samples were sequenced as controls. RNA-Seq from G3 medulloblastomas after restoration of Atoh1 expression.

Dataset Information

Targeting Group3 Medulloblastoma by the anti-PRUNE-1 and anti-LSD1- KDM1A molecules augments their potential therapeutic value.

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