The YY1-CCDC43-ADRM1 Signaling Axis Promotes Tumorigenesis, Invasion and Metastasis of Gastric Cancer

Abstract

Background: Previous studies have showed an association of coiled-coil domain-containing (CCDC) genes with cancers. Our studies also found that CCDC43 is highly expressed in colorectal cancer. However, the expression patterns and molecular mechanisms of CCDC43 in gastric cancer (GC) have not been elucidated. Methods: We analyzed the CCDC43 gene expression in GC samples and adjacent noncancerous mucosa tissues by immunohistochemistry, western blot and quantitative real-time PCR (qPCR) analysis. Additionally, we utilized isobaric Tag for Relative and Absolute Quantitation (iTRAQ) to identify differentially expressed proteins in CCDC43-overexpressing cells. Chromatin immunoprecipitation (ChIP) assay and luciferase reporter assay were used to investigate the role of transcription factor YY1 in promoting the expression of CCDC43 and ADRM1. Findings: CCDC43 was overexpressed in gastric tissues. CCDC43 expression was closely related to tumor differentiation, lymph-node-metastasis and prognosis of gastric cancer. Over-expression of CCDC43 promoted the proliferation, invasion and metastasis of GC cells. CCDC43 could upregulate and stabilize ADRM1, resulting in the degradation of ubiquitin-mediated proteasomal. While, inhibition of ADRM1 could reverse the function of CCDC43 in GC both in vitro and in vivo. In addition, our data demonstrated that transcription factor YY1 directly bound to the CCDC43 gene promoter, leading to over-expression of CCDC43 and ADRM1. We also confirmed that YY1, CCDC43 and ADRM1 proteins were positively and correlatively expressed in human GC tissue compared with adjacent noncancerous tissues. Interpretation: Our findings suggest that the YY1-CCDC43-ADRM1 axis provides a potential therapeutic target of GC. Funding: Natural Science Foundation of China. Declaration of Interest: The authors declare that they have no conflict of interest. Ethical Approval: Samples from surgical removal of gastric cancer from 2019 were selected from the Department of Surgery of Nanfang Hospital, Southern Medical University. The Ethics Committee of the Southern Medical University, China, approved our experimental protocols. Mice were maintained in a specific pathogen-free environment. All in vivo experiments were approved by the Institutional Animal Care and Use Committee of Southern Medical University.