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CREB1 contributes colorectal cancer cell plasticity by regulating lncRNA CCAT1 and NF-κB pathways

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Abstract

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-κB 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-κB 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-κB pathways, providing a critical insight into a combined strategy for CREB1-targeted tumor therapies.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31970604, 31900903, 31770879), the Major Research Plan of the National Natural Science Foundation of China (91940000), the National Key Research and Development Program of China (2017YFA0504400), in part by the Guangdong Province Key Laboratory of Computational Science (13lgjc05), the Guangdong Province Computational Science Innovative Research Team (14lgjc18), and the Fundamental Research Funds for the Central Universities (20lgpy112, 2021qntd26).

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  1. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China

    Bin Li, Jiayi Ye, Chenmin Zhang, Jie Zhou, Qiaojuan Huang, Peng Yu, Shurong Liu, Qiao Lin, Yuxia Luo, Hui Zhou, Jianhua Yang & Lianghu Qu

  2. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China

    Lisi Zheng

  3. Guangzhou Quality Supervision and Testing Institute, Guangzhou, 511400, China

    Yanhua Guo

  4. Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510663, China

    Luqin Wang

  5. The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, China

    Jiayi Ye, Jie Zhou, Qiao Lin & Jianhua Yang

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Li, B., Zheng, L., Ye, J. et al. CREB1 contributes colorectal cancer cell plasticity by regulating lncRNA CCAT1 and NF-κB pathways. Sci. China Life Sci. 65, 1481–1497 (2022). https://doi.org/10.1007/s11427-022-2108-x

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