Journal Article

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

Ye, Jiayi, Zhou, Jie, Yu, Peng, Yang, Jianhua, Zheng, Lisi, Zhou, Hui, Guo, Yanhua, Liu, Shurong, Lin, Qiao, Li, Bin, Qu, Lianghu, Wang, Luqin, Luo, Yuxia, Zhang, Chenmin, Huang, Qiaojuan

2022

Overview

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.

• Publisher: Science China Press,Springer Nature B.V
• Subject: Biomedical and Life Sciences / Cancer / Cancer therapies / Cell Line, Tumor / Cell Movement - genetics / Cell Plasticity - genetics / Cell Plasticity - physiology / Cell proliferation / Cell Proliferation - genetics / Colorectal cancer / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - physiopathology / Cover Article / Cyclic AMP Response Element-Binding Protein - genetics / Cyclic AMP Response Element-Binding Protein - metabolism / Epithelial-Mesenchymal Transition - genetics / Epithelial-Mesenchymal Transition - physiology / Gene Expression Regulation, Neoplastic / Humans / Inflammation / Life Sciences / Mesenchyme / Myc protein / NF-kappa B - genetics / NF-kappa B - metabolism / NF-κB protein / Non-coding RNA / Phenotypes / Plastic properties / Plasticity / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / Signal transduction / Tumors