Epithelial-to-mesenchymal transition (EMT) that endows cancer cells with increased invasive and migratory capacity enables cancer dissemination and metastasis. This process is tightly associated with metabolic reprogramming acquired for rewiring cell status and signaling pathways for survival in dietary insufficiency conditions. However, it remains largely unclear how transcription factor (TF)-mediated transcriptional programs are modulated during the EMT process. Here, we reveal that depletion of a key epithelial TF, (E74-like factor-3), triggers a transforming growth factor β (TGF-β) signaling activation-like mesenchymal transcriptomic profile and metastatic features linked to the aminoacyl-tRNA biogenesis pathway. Moreover, the transcriptome alterations elicited by depletion perfectly resemble an ATF4-dependent weak response to amino acid starvation. Intriguingly, we observe an exclusive enrichment of ELF3 and ATF4 in epithelial and TGF-β-induced or -depletion-elicited mesenchymal enhancers, respectively, with rare co-binding on altered enhancers. We also find that the upregulation of aminoacyl-tRNA synthetases and some mesenchymal genes upon amino acid deprivation is diminished in -depleted cells. In sum, the loss of ELF3 binding on epithelial enhancers and the gain of ATF4 binding on the enhancers of mesenchymal factors and amino acid deprivation responsive genes facilitate the loss of epithelial cell features and the gain of TGF-β-signaling-associated mesenchymal signatures, which further promote lung cancer cell metastasis.

中文翻译：

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ELF3和ATF4转录轴的转换编程氨基酸不足相关的上皮间质转化


上皮间质转化（EMT）赋予癌细胞增强的侵袭和迁移能力，从而促进癌症扩散和转移。这一过程与代谢重编程密切相关，代谢重编程是为了在饮食不足的情况下重新连接细胞状态和信号通路以求生存。然而，目前仍不清楚转录因子（TF）介导的转录程序在 EMT 过程中是如何调节的。在这里，我们揭示了关键上皮 TF（E74 样因子 3）的耗竭会触发转化生长因子 β (TGF-β) 信号激活样间充质转录组谱和与氨酰基-tRNA 生物发生途径相关的转移特征。此外，由耗竭引起的转录组改变完全类似于 ATF4 依赖性的对氨基酸饥饿的弱反应。有趣的是，我们观察到 ELF3 和 ATF4 分别在上皮和 TGF-β 诱导或耗竭引起的间充质增强子中独家富集，而与改变的增强子很少发生共结合。我们还发现，在氨基酸缺失的细胞中，氨酰-tRNA 合成酶和一些间充质基因的上调减弱。总之，上皮增强子上 ELF3 结合的丧失以及间充质因子和氨基酸剥夺反应基因增强子上 ATF4 结合的增加，促进了上皮细胞特征的丧失和 TGF-β 信号传导相关间充质特征的获得，进一步促进肺癌细胞的转移。