Deep computational analysis details dysregulation of eukaryotic translation initiation complex eIF4F in human cancers.
Deep computational analysis details dysregulation of eukaryotic translation initiation complex eIF4F in human cancers.
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DOI：
10.1016/j.cels.2021.07.002
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发表时间：
2021-09-22
期刊：
影响因子：
9.3
通讯作者：
Wagner G
中科院分区：
文献类型：
--
作者：
Wu S;Wagner G
eIF 4F在人类癌症中发挥着不同的作用，这使得对其在肿瘤类型中的功能和调控影响的总体理解的发展变得复杂。通常，eIF 4F驱动从mRNA 5'端（帽）起始，并且由eIF 4G 1、eIF 4A 1和帽结合eIF 4 E组成。不需要eIF 4 E，可以从内部核糖体进入位点（IRES）进行帽非依赖性起始。通过分析大型公共数据集，我们发现癌症选择性过表达EIF 4G 1超过EIF 4 E。这种表达不平衡支持EIF 4G 1作为癌症患者的预后指标。它还减弱了通常通过在健康组织中的帽依赖性起始以组织特异性方式调节的“管家”途径，并加强了在帽非依赖性背景下对癌症优选途径的调节。帽非依赖性起始机制可归因于eIF 4G 1过度磷酸化，其促进与eIF 4A 1的结合，并降低eIF 4 E的可用性。总的来说，这些发现揭示了eIF 4F功能失调的新模型，并突出了癌症中cap-（in）依赖性起始的临床相关性。Wu和瓦格纳利用mRNA/蛋白质组学相关性，使用大型公共数据集研究人类癌症中的翻译起始复合物eIF 4 F。他们发现癌症中EIF 4G 1和EIF 4 E的选择性表达不平衡，与“管家”基因的帽依赖性启动减弱和癌症偏好基因的帽非依赖性启动增强有关。
eIF4F plays diverse roles in human cancers, which complicate development of an overarching understanding of its functional and regulatory impacts across tumor types. Typically, eIF4F drives initiation from the mRNA 5’ end (cap), and is composed of eIF4G1, eIF4A1, and cap-binding eIF4E. Cap-independent initiation is possible without eIF4E, from internal ribosomal entry sites (IRESs). By analyzing large public datasets, we found that cancers selectively overexpress EIF4G1 more than EIF4E. That expression imbalance supports EIF4G1 as a prognostic indicator in patients with cancer. It also attenuates “house-keeping” pathways that are usually regulated in a tissue-specific manner via cap-dependent initiation in healthy tissues, and reinforces regulation of cancer-preferred pathways in cap-independent contexts. Cap-independent initiation is mechanistically attributable to eIF4G1 hyperphosphorylation that promotes binding to eIF4A1, and reduced eIF4E availability. Collectively, these findings reveal a novel model of dysregulated eIF4F function, and highlight the clinical relevance of cap-(in)dependent initiation in cancer. Wu and Wagner leverage mRNA/proteomic correlations to investigate the translation initiation complex eIF4F in human cancers using large public datasets. They find selective expression imbalance of EIF4G1 and EIF4E in cancer, associated with attenuated cap-dependent initiation for “house-keeping” genes, and reinforced cap-independent initiation for cancer-preferred genes.
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