Circ_CEA promotes the interaction between the p53 and cyclin-dependent kinases 1 as a scaffold to inhibit the apoptosis of gastric cancer

Abstract

Circular RNAs (circRNAs) have been reported to play essential roles in tumorigenesis and progression. This study aimed to identify dysregulated circRNAs in gastric cancer (GC) and investigate the functions and underlying mechanism of these circRNAs in GC development. Here, we identify circ_CEA, a circRNA derived from the back-splicing of CEA cell adhesion molecule 5 (CEA) gene, as a novel oncogenic driver of GC. Circ_CEA is significantly upregulated in GC tissues and cell lines. Circ_CEA knockdown suppresses GC progression, and enhances stress-induced apoptosis in vitro and in vivo. Mechanistically, circ_CEA interacts with p53 and cyclin-dependent kinases 1 (CDK1) proteins. It serves as a scaffold to enhance the association between p53 and CDK1. As a result, circ_CEA promotes CDK1-mediated p53 phosphorylation at Ser315, then decreases p53 nuclear retention and suppresses its activity, leading to the downregulation of p53 target genes associated with apoptosis. These findings suggest that circ_CEA protects GC cells from stress-induced apoptosis, via acting as a protein scaffold and interacting with p53 and CDK1 proteins. Combinational therapy of targeting circ_CEA and chemo-drug caused more cell apoptosis, decreased tumor volume and alleviated side effect induced by chemo-drug. Therefore, targeting circ_CEA might present a novel treatment strategy for GC.

Emerging roles of circular RNAs in tumorigenesis, progression, and treatment of gastric cancer

“…Circ_CEA is significantly upregulated in GC tissues and cell lines, wherein it serves as a scaffold to facilitate the interaction between p53 and cyclin-dependent kinase 1, which phosphorylates p53 at Ser315, decreases its retention in the nucleus, and suppresses its activity. Consequently, p53 target genes associated with apoptosis are downregulated and GC cell apoptosis is inhibited [ 37 ].…”

Cellular senescence: A potential mode of circular RNAs regulating prostate cancer

“…CircCEA may act as a scaffold between p53 and cyclin‐dependent kinases 1 (CDK1), according to a study. It promoted CDK1‐mediated p53 phosphorylation, which decreased p53's nuclear retention and hindered its function, ultimately resulting in p53 downregulation 108 . Liu et al 109 found that circMYH9 disrupted the stability of p53 pre‐mRNA by recruiting hnRNPA2B1, which played a stabilizing role in the nucleus by binding to N6‐methyladenosine sites of p53 pre‐mRNA.…”

Circ_0003945: an emerging biomarker and therapeutic target for human diseases

“…(2) CircRNAs serve as molecular sponges for proteins, particularly RNA-binding proteins, regulating the transcription or translation of downstream target genes ( 22 , 23 ). (3) CircRNAs function as protein scaffolds facilitating interactions between specific proteins ( 16 , 24 ). (4) CircRNAs possess translational capacity, producing peptides that exert biological functions ( 25 – 27 ).…”