CREB1 contributes colorectal cancer cell plasticity by regulating lncRNA CCAT1 and NF-κB pathways
CREB1 contributes colorectal cancer cell plasticity by regulating lncRNA CCAT1 and NF-κB pathways
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CREB1通过调控lncRNA、CCAT1和NF-κB通路促进结直肠癌细胞可塑性
DOI：
10.1007/s11427-022-2108-x
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发表时间：
2022-06-10
影响因子：
9.1
通讯作者：
Qu, Lianghu
中科院分区：
文献类型：
--
作者：
Li, Bin;Zheng, Lisi;Qu, Lianghu
CREB 1基因编码一种异常的多效性转录因子，在人类癌症中经常失调。CREB 1可以调节肿瘤细胞的增殖和/或迁移状态;然而，这种开关参与细胞可塑性的分子基础尚未完全理解。在这里，我们首先表明，敲除CREB 1触发上皮间质转化（EMT）的显着效果，并导致HCT 116结直肠癌细胞中增殖抑制和运动增强的发生。通过监测45种细胞信号通路的活性，我们发现多种生长相关通路显著下降，而包括NF-κ B在内的炎症通路在CREB 1野生型和敲除细胞之间的比较中大幅上调。从机制上讲，CREB 1敲除的细胞由于致癌lncRNA CCAT 1的CREB 1依赖性转录受损而显示MYC下调。有趣的是，共激活因子CBP/p300对CREB 1和p65的不平衡竞争导致CREB 1被破坏的细胞中NF-κ B通路的激活，这诱导了癌细胞的明显EMT表型。总之，这些研究通过调节lncRNA CCAT 1和NF-κ B途径确定了CREB 1在CRC细胞可塑性中的先前未知机制，为CREB 1靶向肿瘤治疗的联合策略提供了重要见解。
The CREB1 gene encodes an exceptionally pleiotropic transcription factor that frequently dysregulated in human cancers. CREB1 can regulate tumor cell status of proliferation and/or migration; however, the molecular basis for this switch involvement in cell plasticity has not fully been understood yet. Here, we first show that knocking out CREB1 triggers a remarkable effect of epithelial-mesenchymal transition (EMT) and leads to the occurrence of inhibited proliferation and enhanced motility in HCT116 colorectal cancer cells. By monitoring 45 cellular signaling pathway activities, we find that multiple growth-related pathways decline significantly while inflammatory pathways including NF-kappa B are largely upregulated in comparing between the CREB1 wild-type and knocked out cells. Mechanistically, cells with CREB1 knocked out show downregulation of MYC as a result of impaired CREB1-dependent transcription of the oncogenic lncRNA CCAT1. Interestingly, the unbalanced competition between the coactivator CBP/p300 for CREB1 and p65 leads to the activation of the NF-kappa B pathway in cells with CREB1 disrupted, which induces an obvious EMT phenotype of the cancer cells. Taken together, these studies identify previously unknown mechanisms of CREB1 in CRC cell plasticity via regulating lncRNA CCAT1 and NF-kappa B pathways, providing a critical insight into a combined strategy for CREB1-targeted tumor therapies.