Dataset Information

Proteomic research on effect of EIF4A1 inhibition in MYC-amplified Group 3 medulloblastoma

ABSTRACT: As the most life-threatening subtype of pediatric medulloblastoma (MB), MYC-amplified Group 3 (G3) MB lacks effective and selective therapeutics. We tried to indirectly target MYC (oncogenic driver and cancer-dependent molecule) production via inhibiting translational machinery. Through multiple datasets analyses on components of eIF4F (eukaryotic translation initiation factor 4F) complex, we found that EIF4A1 (major component with RNA helicase activity) has relatively higher expression level and the closest positive correlation with MYC in G3-MB among normal control and other 3 subtypes (e.g., WNT, SHH and G4). Both in vitro and in vivo experiments with MYC-amplified G3-MB cell lines showed effective growth inhibition upon EIF4A1 knockout or inhibitor treatment. Further FACS analysis found decreased cell proliferation and enhanced apoptosis on EIF4A1 inhibitor treatment. To explore the mechanisms of EIF4A1 inhibition on arresting MYC-amplified G3-MB, we performed the whole proteome analyses on corresponding MB cells treated with EIF4A1 inhibitor.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yujie Tang

PROVIDER: PXD022014 | iProX | Thu Oct 15 00:00:00 BST 2020

REPOSITORIES: iProX

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Publications

Effective Inhibition of <i>MYC</i>-Amplified Group 3 Medulloblastoma Through Targeting EIF4A1.

Zhao Yang Y Li Tiantian T Tian Shuaiwei S Meng Wei W Sui Yi Y Yang Jian J Wang Baocheng B Liang Zhuangzhuang Z Zhao Heng H Han Yipeng Y Tang Yujie Y Zhang Lei L Ma Jie J

Cancer management and research 20201203

<h4>Purpose</h4>In medulloblastoma (MB), group 3 (G3) patients with <i>MYC</i> amplification tend to exhibit worse prognosis, thus creating a need for novel effective therapies. As the driver and crucial dependency for <i>MYC</i>-amplified G3-MB, <i>MYC</i> has been proven to be a prospective therapeutic target. Here, we aimed to identify novel effective therapeutic strategies against <i>MYC</i>-amplified G3-MB via targeting <i>MYC</i> translation.<h4>Materials and methods</h4>Major components o ...[more]

PMID: 33299354

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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.

Dataset Information

Proteomic research on effect of EIF4A1 inhibition in MYC-amplified Group 3 medulloblastoma

Publications

Effective Inhibition of <i>MYC</i>-Amplified Group 3 Medulloblastoma Through Targeting EIF4A1.

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