Systematical analysis reveals a strong cancer relevance of CREB1-regulated genes

Tianyu Zheng,Xi Xiang,Jiaying Yu,Peng Han,Yang Liu,Fengping Xu,Kunli Qu,Siyuan Li,Huanming Yang,Yonglun Luo,Zhe Xu,Jinrong Huang,Zhanying Dong,Marja Jäättelä,Bin Liu

doi:10.1186/s12935-021-02224-z

Abstract

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.

Highlights

cyclic-AMP response element-binding protein 1 (CREB1)(cAMP response element-binding protein) belongs to a family of transcription factors whose activities are induced by increased intracellular cAMP [1, 2]
The same trend is observed when we summarize the list of differentially expressed genes (DEG) shared by all paired comparisons and with opposite expression profiles between CREB1 KO clones vs wild type (WT) cells (KO vs WT) and CREB1 rescue cells vs CREB1 KO clones (Rescue vs KO) (Fig. 2C)
CREB1 is a multi-functional transcription factor whose activity is tightly regulated by the level of the intracellular cAMP

Summary

Introduction

CREB1(cAMP response element-binding protein) belongs to a family of transcription factors whose activities are induced by increased intracellular cAMP [1, 2]. More than 4000 CREB1 affinity bonded promoters have been identified by Chip-seq, only 339 genes’ promoters contain both CRE and TATA box, and less than 100 genes are validated as CREB1 target genes in a cAMP-responsive manner [7]. This suggests that many other putative CREB1 target genes might be regulated in a cAMP-independent or even CRE-independent manner. Given that many transcription factors are downstream targets of

Methods

Results

Conclusion