Zheng Tianyu, Huang Jinrong, Xiang Xi, Li Siyuan, Yu Jiaying, Qu Kunli, Xu Zhe, Han Peng, Dong Zhanying, Liu Yang, Xu Fengping, Yang Huanming, Jäättelä Marja, Luo Yonglun, Liu Bin
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
Lars Bolund Institute of Regenerative Medicine, Qingdao-Europe Advanced Institute for Life Sciences, BGI-Qingdao, BGI-Shenzhen, Qingdao, 266555, China.
Cancer Cell Int. 2021 Oct 12;21(1):530. doi: 10.1186/s12935-021-02224-z.
The transcription factor cyclic-AMP response element-binding protein 1 (CREB1) responds to cAMP level and controls the expression of target genes, which regulates nutrition partitioning. The promoters of CREB1-targeted genes responsive to cAMP have been extensively investigated and characterized with the presence of both cAMP response element and TATA box. Compelling evidence demonstrates that CREB1 also plays an essential role in promoting tumor development. However, only very few genes required for cell survival, proliferation and migration are known to be constitutively regulated by CREB1 in tumors. Their promoters mostly do not harbor any cAMP response element. Thus, it is very likely that CREB1 regulates the expressions of distinct sets of target genes in normal tissues and tumors. The whole gene network constitutively regulated by CREB1 in tumors has remained unrevealed. Here, we employ a systematical and integrative approach to decipher this gene network in the context of both tissue cultured cancer cells and patient samples. We combine transcriptomic, Rank-Rank Hypergeometric Overlap, and Chipseq analysis, to define and characterize CREB1-regulated genes in a multidimensional fashion. A strong cancer relevance of those top-ranked targets, which meet the most stringent criteria, is eventually verified by overall survival analysis of cancer patients. These findings strongly suggest the importance of genes constitutively regulated by CREB1 for their implicative involvement in promoting tumorigenesis.
转录因子环磷酸腺苷反应元件结合蛋白1（CREB1）对环磷酸腺苷（cAMP）水平作出反应并控制靶基因的表达，从而调节营养分配。对cAMP有反应的CREB1靶向基因的启动子已得到广泛研究，并因其同时存在cAMP反应元件和TATA盒而得以表征。有力证据表明，CREB1在促进肿瘤发展中也起着至关重要的作用。然而，已知在肿瘤中只有极少数细胞存活、增殖和迁移所需的基因受CREB1组成型调控。它们的启动子大多不含有任何cAMP反应元件。因此，CREB1很可能在正常组织和肿瘤中调节不同组别的靶基因表达。CREB1在肿瘤中组成型调控的整个基因网络仍未被揭示。在这里，我们采用系统综合的方法，在组织培养的癌细胞和患者样本的背景下破译这个基因网络。我们结合转录组学、秩-秩超几何重叠分析和芯片测序分析，以多维方式定义和表征CREB1调控的基因。通过癌症患者的总生存分析最终验证了那些符合最严格标准的顶级靶点与癌症的高度相关性。这些发现强烈表明，CREB1组成型调控的基因对于其在促进肿瘤发生中的潜在作用具有重要意义。
