1. Academic Validation
  2. Effective Inhibition of MYC-Amplified Group 3 Medulloblastoma Through Targeting EIF4A1

Effective Inhibition of MYC-Amplified Group 3 Medulloblastoma Through Targeting EIF4A1

  • Cancer Manag Res. 2020 Dec 3;12:12473-12485. doi: 10.2147/CMAR.S278844.
Yang Zhao  # 1 Tiantian Li  # 2 Shuaiwei Tian  # 1 Wei Meng 1 Yi Sui 2 Jian Yang 1 Baocheng Wang 1 Zhuangzhuang Liang 1 Heng Zhao 1 Yipeng Han 1 Yujie Tang 1 2 Lei Zhang 2 Jie Ma 1
Affiliations

Affiliations

  • 1 Department of Pediatric Neurosurgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
  • 2 Key Laboratory of Cell Differentiation and Apoptosis of the National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
  • # Contributed equally.
Abstract

Purpose: In medulloblastoma (MB), group 3 (G3) patients with MYC amplification tend to exhibit worse prognosis, thus creating a need for novel effective therapies. As the driver and crucial dependency for MYC-amplified G3-MB, MYC has been proven to be a prospective therapeutic target. Here, we aimed to identify novel effective therapeutic strategies against MYC-amplified G3-MB via targeting MYC translation.

Materials and methods: Major components of translation initiation complex eIF4F were subjected to MB tumor dataset analysis, and EIF4A1 was identified to be a potential therapeutic target of MYC-amplified G3-MB. Validation was performed through genetic or pharmacological approaches with multiple patient-derived tumor models of MYC-amplified G3-MB in vitro and in vivo. Underlying mechanisms were further explored by Western blot, quantitative Real-Time PCR and mass spectrometry (MS) analyses.

Results: MB tumor datasets analyses showed that EIF4A1 was significantly up-regulated in G3-MB patients relative to normal cerebella, positively correlated with MYC in G3-MB at transcriptional level and a crucial Cancer dependency in MYC-amplified G3-MB cells. Targeting EIF4A1 with a CRISPR/Cas9 approach or small-molecule inhibitor silvestrol effectively attenuated growth in multiple preclinical models of MYC-amplified G3-MB via blocking proliferation and inducing Apoptosis. Mechanistically, EIF4A1 inhibition effectively impeded MYC expression at translational level, and its potency was positively associated with MYC level. Whole-proteome MS analysis of silvestrol-treated cells further unveiled other biological functions and pathways influenced by EIF4A1 inhibition.

Conclusion: Our investigation shows that interrupting MYC translation by EIF4A1 inhibition could be a potential effective therapeutic approach when treating patients with MYC-amplified G3-MB.

Keywords

EIF4A1; MYC-amplified group 3 medulloblastoma; Silvestrol; eIF4F complex; translation inhibition.

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