The RNA binding protein Musashi1 regulates a network of cell cycle genes in Group 4 medulloblastoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB40550 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR4647590.fastq.gz | Fastqsanger.gz | |||
| ERR4647600.fastq.gz | Fastqsanger.gz | |||
| ERR4647591.fastq.gz | Fastqsanger.gz | |||
| ERR4647592.fastq.gz | Fastqsanger.gz | |||
| ERR4647593.fastq.gz | Fastqsanger.gz |
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Project description:Medulloblastoma is the most common malignant brain tumor in children. Treatment with surgery, irradiation, and chemotherapy has improved survival in recent years, but patients are frequently left with devastating neurocognitive and other sequelae. Patients in molecular subgroups 3 and 4 still experience a high mortality rate. To identify new pathways contributing to medulloblastoma development and create new routes for therapy, we have been studying oncogenic RNA-binding proteins. We defined Musashi1 (Msi1) as one of the main drivers of medulloblastoma development. The high expression of Msi1 is prevalent in Group 4 and correlates with poor prognosis while its knockdown disrupted cancer-relevant phenotypes. Genomic analyses (RNA-seq and RIP-seq) indicated that cell cycle and division are the main biological categories regulated by Msi1 in Group 4 medulloblastoma. The most prominent Msi1 targets include CDK2, CDK6, CCND1, CDKN2A, and CCNA1. The inhibition of Msi1 with luteolin affected the growth of CHLA-01 and CHLA-01R Group 4 medulloblastoma cells and a synergistic effect was observed when luteolin and the mitosis inhibitor, vincristine, were combined. These findings indicate that a combined therapeutic strategy (Msi1 + cell cycle/division inhibitors) could work as an alternative to treat Group 4 medulloblastoma.
| S-EPMC8750343 | biostudies-literature
Project description:Transcripts regulated by Musashi-1 (MSI1) are explored through shRNA-mediated knockdown of MSI1 in SU_MB002 medulloblastoma cells.
2020-02-01 | GSE126337 | GEO
Project description:RIP-chip analysis to identify mRNA preferentially associated with Msi1 protein. RIP-Chip experiments were performed on two biologically replicated samples transfected with the BAP-Msi1 construct and a control sample from cells transfected with the BAP-Control construct. A total of 8 microarrays were carried on using technical replicates of BAP-Msi1 vs. BAP-Control for each dye orientation.
2011-07-25 | E-GEOD-30904 | biostudies-arrayexpress
Project description:RIP-chip analysis to identify mRNA preferentially associated with Msi1 protein.
2011-07-26 | GSE30904 | GEO
Project description:Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with group 3 (G3) MB representing the most aggressive subgroup associated with a poor prognosis and a remarkable ability to resist upfront multimodal therapy. Despite a low mutational burden of disease and MYC amplification identified as a independent factor associated with poor survivorship, efforts to target the MYC has met with limited therapeutic success. Consequently alternative mediators associated with the aggressive phenotype of G3 MB continues as a common goal within the MB community. Here we show how the neural stem cell determinant Musashi 1 (MSI1) is a central and vital moderator of G3 MB in both a MYC amplified mouse model of G3 MB and patient derived xenografts (PDX). Specifically, we modified the MYC amplified and p53 mutated (MP) mouse model of G3 MB to generate Msi1 conditional knockout mice (Msi1flox/flox), which led to the observation that MSI1 is required for tumor initiation of MP tumors. To identify the translational potential of these findings, we employed shRNA against Msi1 in multiple PDX lines, observing a striking deficit in multiple key stem cell features including self-renewal, proliferation, and failure to progress through the cell cycle. Notably, Msi1 inhibition resulted in a failure of tumor initiation, translating to a significantly prolonged survival, reaffirming the essential role for MSI1 in G3 MB. To determine how MSI1 symphonizes the anarchic post-transcriptional landscape of G3MB, we differentially analyzed the MSI1 binding sites in normal neural stem cells and G3 MB and subsequently compared the MSI1-binding transcriptome, and proteome following Msi1 inhibition. Comparative analysis suggested an integral role for post-transcriptional regulators, such as MSI1 and its binding prey mRNA, as a therapeutic target. Here we propose the neural RNA binding protein MSI1, as a master regulator, hijacked from its normal neural developmental function, orchestrating the aberrant translational landscape of G3 MB.
2022-07-19 | GSE134597 | GEO
Project description:RNA binding proteins (RBPs) function as master regulators of gene expression. Alterations in their expression levels and function are often observed in tumors with numerous oncogenic RBPs identified in recent years. Musashi1 (Msi1) is an RBP and stem cell marker gene that controls the balance between self-renewal and proliferation. High Msi1 levels have been observed in multiple tumor types including glioblastoma and are often associated with poor patient outcomes. Msi1 knockdown is known to affect numerous cancer phenotypes and to prevent growth of different tumor types. To dissect Msi1’s main contributions to glioblastoma development, we conducted a comprehensive genomic analysis. We identified a network of cell cycle/division and DNA replication genes and established these processes as its core functions. Msi1 controls this gene network via two mechanisms: direct interaction and indirect regulation mediated by the transcription factors E2F2 and E2F8. We corroborated Msi1’s impact on these processes and determined that glioblastoma lines with Msi1 KO display increased sensitivity to cell cycle and DNA replication inhibitors. As Msi1 inhibitors have been identified, a drug combination strategy (Msi1 + cell cycle/DNA replication inhibitors) could be a viable route to treat glioblastoma.
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Project description:Groups (Grp) 3 and 4 are aggressive molecular subgroups of medulloblastoma (MB), with high rates of leptomeningeal dissemination. To date, there is still a paucity of biomarkers for these subtypes of MBs. In this study, we investigated the clinical significance and biological functions of MSI1 in Grp3/Grp4-MBs. To that, we identified that the MSI1 knockdown sensitized D283 Med cells to cisplatin treatment by enhancing cell apoptosis and modulated cancer-related pathways. The results of the present demonstrate that MSI1 may play a role as biomarker for Grp3/Grp4-MBs. In addition, MSI1 knockdown combined with cisplatin may offer a potential strategy to be further explored in Grp3/Grp4-MBs.
2024-03-03 | GSE226733 | GEO
Project description:Transcripts bound to Musashi-1 (MSI1) are explored in Group 3 medulloblastoma (G3 MB) and neural stem cells harvested from the cerebellar portion of a embryonal brain
2022-10-28 | GSE126263 | GEO
Project description:Musashi1 (Msi1) is a highly conserved RNA binding protein that is required during the development of the nervous system. Msi1 has a role in neural stem cells, controlling the balance between self-renewal and differentiation. Msi1 has also been implicated in cancer, being highly expressed in multiple tumor types. In this study, we analyzed Msi1 expression in a large cohort of medulloblastoma samples and showed that Msi1 is highly expressed in tumor tissue compared to normal cerebellum and that high Msi1 expression is associated with a poor prognosis. Using a nude mouse xenograft model, we demonstrate that Msi1 is important for tumor growth. We then used RIP-chip (ribonucleoprotein immunoprecipitation followed by microarray analysis) to identify mRNA targets of Msi1 in medulloblastoma. In conclusion, our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target. RIP-Chip analysis to identify mRNA preferentially associated with Msi1 protein. RIP-Chip experiments were performed on two biologically replicated samples. A total of 8 microarrays were carried on using technical replicates of Msi1 antibody vs. prebleed serum for each dye orientation. We prepared two biological replicates for two different arrays. Each array consisted of 4 microarrays with 2 replicates for each dye orientation.
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Project description:RIP-Chip analysis of Msi1 and identification of preferentially associated mRNAs. Keywords: RIP-Chip
2008-07-19 | GSE12171 | GEO