Chromobox 4 (CBX4) promotes tumor progression and stemness via activating CDC20 in gastric cancer

Journal of Gastrointestinal Oncology

article

Wen Li¹  Honghui Chen¹  Zhenggen Wang¹  Jingjing Liu¹  Xinan Lei¹  Wen Chen¹ 

[1] The Second Affiliated Hospital, Department of Gastroenterology, Hengyang Medical School, University of South China

关键词: Chromobox homolog 4 (CBX4);    CDC20;    tumor stemness;    prognosis;    gastric cancer (GC);   

DOI  :  10.21037/jgo-22-549

学科分类：肿瘤学

来源: Pioneer Bioscience Publishing Company

【 摘 要 】

Background: The Chromobox homolog 4 (CBX4) has been found to be overexpressed in multiple malignancies. However, the associations between CBX4 and gastric cancer (GC) have remained unclear. This study aimed to determine the biological roles of CBX4 in GC and identify effective therapeutic targets. Methods: The 3-(4,5-dimethylthiazol-2-yl) (MTT) assays were used to screen CBX family members. Differential analysis was utilized to evaluate the CBX4 levels. Kaplan-Meier analysis was used to perform prognostic analysis. Western blotting assay, quantitative polymerase chain reaction (qPCR) assay and immunohistochemistry (IHC) were used to assess CBX4 expressions. Colony formation assay, Cell Counting Kit-8 (CCK-8) assay, and Transwell assay were used to assess progression features of cells. The tail vein injection model was utilized to determine the metastatic efficacy of GC cells. Tumor sphere formation assay was used to assess tumor stemness maintenance ability. Chromatin immunoprecipitation (ChIP)-qPCR assay was used to evaluate the associations between CBX4 and CDC20. A subcutaneous tumor model was used to assess the in vivo growth ability of GC. Results: The MTT assay revealed that only CBX4 inhibition could lead to notable restriction of GC growth, as compared to others. Differential analysis suggested that CBX4 was upregulated in tumor samples relative to normal tissues. Less favorable overall survival (OS) outcomes were noticed in GC patients with high CBX4 in comparison to those with low CBX4. High CBX4 could notably enhance cell proliferation capacity, migration ability, and in vivo metastatic efficacy. Gene set enrichment analysis (GSEA) indicated the relationships between CBX4 and GC stemness, and CBX4 overexpression could remarkably elevate self-renewal ability of GC cells. In addition, CBX4 could mainly promote CDC20 messenger RNA (mRNA) levels, and targeting CBX4 suppressed the relative CDC20 levels. The ChIP-qPCR assay further demonstrated that CBX4 coordinated with H3K4me3 to bind at the CDC20 promoter region. Additionally, CBX4 depended on CDC20 to drive GC growth. Lastly, downregulated CBX4 could notably inhibit the growth of GC in vivo. Conclusions: This study highlights the oncogenic roles of CBX4 in GC. CBX4 activates CDC20 to maintain stemness features of GC, thereby creating therapeutic vulnerabilities in the treatment of GC.

【 授权许可】

Unknown