Mohan Prathibha, Pasion Joyce, Ciriello Giovanni, Lailler Nathalie, de Stanchina Elisa, Viale Agnes, van den Berg Anke, Diepstra Arjan, Wendel Hans-Guido, Sanghvi Viraj R, Singh Kamini
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Computational Biology, University of Lausanne, CH-1005 Lausanne, Switzerland.
Cancers (Basel). 2022 May 13;14(10):2397. doi: 10.3390/cancers14102397.
The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We noticed that 4EBP1 gains are genetically linked to gains in neighboring genes, including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K-mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition, and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and the inositol pathway to be the relevant translational targets of 4EBP1. These mRNAs are among the top 200 translation targets and are highly enriched for structure and sequence motifs in their 5'UTR, which depends on the 4EBP1-EIF4E activity. In summary, we identified the translational targets of 4EBP1-EIF4E that facilitate the tumor suppressor function of 4EBP1 in cancer.
真核生物翻译起始因子4E（eIF4E）具有致癌特性，相应地，抑制性的eIF4E结合蛋白（4EBP1）被认为是一种肿瘤抑制因子。4EBP1激活在癌症中的确切分子效应仍不清楚。令人惊讶的是，4EBP1是乳腺癌和肺癌中基因组拷贝数增加（染色体8p11）的一个靶点。我们注意到4EBP1的增加与邻近基因（包括WHSC1L1和FGFR1）的增加存在遗传关联。我们的结果表明，FGFR1的增加通过PI3K介导的在Thr37/46、Ser65和Thr70位点的磷酸化作用来减弱4EBP1的功能。这意味着在乳腺癌和肺癌中，染色体8p11增加的遗传靶点不是4EBP1，而是FGFR1。因此，这些肿瘤对FGFR1和PI3K抑制表现出增加的敏感性，这是通过恢复4EBP1的肿瘤抑制功能而产生的一种治疗脆弱性。核糖体分析揭示了参与胰岛素信号传导、葡萄糖代谢和肌醇途径的基因是4EBP1的相关翻译靶点。这些mRNA属于前200个翻译靶点，并且在其5'非翻译区（5'UTR）的结构和序列基序中高度富集，这取决于4EBP1 - eIF4E的活性。总之，我们确定了4EBP1 - eIF4E的翻译靶点，这些靶点促进了4EBP1在癌症中的肿瘤抑制功能。
