Establishment of a CIMP-associated prognostic model for bladder cancer

Background Bladder cancer (BLCA) is the leading cause of cancer-related morbidity and mortality among urological cancers, with a 5-year survival rate of 30–50% for MIBC. While DNA methyltransferase inhibitors may activate the anti-tumor immune response, the role of CpG island methylator phenotype (CIMP) in BLCA remains unclear. It is urgent to identify valuable risk models to assist in BLCA prognosis and improve the survival rates. Methods Consensus clustering was performed to stratify BLCA patients into different CIMP subgroups. Gene set enrichment analysis (GSEA) analysis were conducted to analyze the potential biological mechanisms mediating CIMP-related carcinogenesis of BLCA. Least absolute shrinkage and selector operation were used to construct a CIMP-associated prognostic model (CPM). Genome-wide DNA methylation analysis was performed to explore the potential methylation changes associated with RPSAP52 knockdown. In vitro experiments including CCK-8 assay, wound-healing assays, and 3D tumor spheroid culture experiment were performed to investigate the potential mechanism of RPSAP52 in promoting the progression of BLCA. Results Two CIMP patterns were obtained after clustering 411 BLCA samples from TCGA, and BLCA patients with CIMP-L status had a significantly worse overall survival (OS) and disease-free survival. Epithelial-mesenchymal transition, and interferon gamma response were enriched in BLCA with CIMP-L via enrichment analysis. In addition, BLCA with CIMP-L exhibited a significantly higher infiltration of twenty-two types of immune cells, but a poorer response to immune checkpoint inhibitors (ICIs). Furthermore, BLCA patients could be significantly divided into low and high-risk groups based on 33 genes included in the CIMP-related prognostic model (CPM), with the nomogram developed to assist in the prediction of BLCA prognosis. Finally, it was found that the RPSAP52 gene in the CPM model was associated with OS and response to ICIs for BLCA. Genome-wide DNA methylation analysis showed that RPSAP52 knockdown in cultured UMUC3 cells induced a significantly increased hypermethylated regions of CpG sites. In vitro experiments confirmed that RPSAP52 expression could significantly influence the proliferation, invasion and migration capacity of BLCA cells. Conclusion The BLCA with CIMP-L indicates a worse prognosis, and the CPM developed in this study might serve as an independent prognostic factor for BLCA.