Effective Inhibition of MYC-Amplified Group 3 Medulloblastoma Through Targeting EIF4A1.
Effective Inhibition of MYC-Amplified Group 3 Medulloblastoma Through Targeting EIF4A1.
复制标题
通过靶向 EIF4A1 有效抑制 MYC 扩增的第 3 组髓母细胞瘤。
DOI：
10.2147/cmar.s278844
复制
发表时间：
2020
影响因子：
3.3
通讯作者：
Ma J
中科院分区：
文献类型：
--
作者：
Zhao Y;Li T;Tian S;Meng W;Sui Y;Yang J;Wang B;Liang Z;Zhao H;Han Y;Tang Y;Zhang L;Ma J
在髓母细胞瘤（MB）中，MYC扩增的第3组（G3）患者往往表现出更差的预后，因此需要新的有效治疗方法。作为MYC扩增的G3-MB的驱动因子和关键依赖性，MYC已被证明是一个有前景的治疗靶点。在这里，我们旨在通过靶向MYC翻译来确定针对MYC扩增的G3-MB的新型有效治疗策略。材料与方法对翻译起始复合物eIF 4F的主要组分进行MB肿瘤数据集分析，并鉴定EIF 4A 1是MYC扩增的G3-MB的潜在治疗靶点。通过遗传学或药理学方法，在体外和体内使用MYC扩增的G3-MB的多个患者来源的肿瘤模型进行验证。通过Western blot、实时定量PCR和质谱（MS）分析进一步探讨了潜在的机制。结果MB肿瘤数据集分析显示，EIF 4A 1在G3-MB患者小脑中表达显著上调，与MYC在转录水平呈正相关，在MYC扩增的G3-MB细胞中具有重要的肿瘤依赖性。用CRISPR/Cas9方法或小分子抑制剂silvestrol靶向EIF 4A 1，通过阻断增殖和诱导凋亡，有效地减弱了MYC扩增的G3-MB的多个临床前模型的生长。从机制上讲，EIF 4A 1抑制有效地抑制了MYC在翻译水平上的表达，其效力与MYC水平正相关。对西司雌酚处理细胞的全蛋白质组MS分析进一步揭示了受EIF 4A 1抑制影响的其他生物学功能和途径。结论我们的研究表明，在治疗MYC扩增的G3-MB患者时，通过抑制EIF 4A 1来中断MYC翻译可能是一种潜在的有效治疗方法。
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.