PDF(Pubmed)
Abstract：
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, ELF3 (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 ELF3 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 ELF3-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 ATF4-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.
摘要：
上皮-间质转化（EMT）赋予癌细胞增加的侵袭和迁移能力，使癌症扩散和转移。该过程与获得的代谢重编程紧密相关，以重新连接细胞状态和信号传导途径，以在饮食不足的情况下存活。然而,目前尚不清楚转录因子(TF)介导的转录程序在EMT过程中如何被调节.在这里，我们揭示了一个关键的上皮TF的消耗，ELF3，触发了TGFβ信号激活样的间充质转录组概况和与氨酰-tRNA生物发生途径相关的转移特征。此外，ELF3耗竭引起的转录组改变完全类似于对氨基酸饥饿的ATF4依赖性弱反应。有趣的是，我们观察到上皮和TGFβ诱导或ELF3耗竭引起的间充质增强剂中ELF3和ATF4的唯一富集，分别,在改变的增强子上具有罕见的共结合。我们还发现，在氨基酸剥夺后，氨酰tRNA合成酶和一些间充质基因的上调在ATF4耗尽的细胞中减少。总之,上皮增强子上ELF3结合的丧失和间充质因子和氨基酸剥夺反应基因的增强子上ATF4结合的增加促进了上皮细胞特征的丧失和TGFβ信号相关的间充质特征的获得，从而进一步促进肺癌细胞的转移。
