Prognostic Role of SETDB2 in Clear Cell Renal Cell Carcinoma: Linking Immune Infiltration, Cuproptosis, and Tumor Suppression

Si Hao Lu,1,* Kui Lui,1,* Yue Qian,2 Wei ye Zhou,3 Ying Ying Mu,4 Wei Zhang2,3 1Department of Nephrology, Air Force Hospital of Western Theater Command, Chengdu, 610000, People’s Republic of China; 2Department of Pathogen Biology, Guizhou Nursing Vocational College, Guiyang, Guizhou, 550000, People’s Republic of China; 3Cell Biology Department, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, People’s Republic of China; 4Department of Pathology, Zunyi Hospital of Traditional Chinese Medicine, Zunyi, Guizhou, 563000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Zhang, Department of Pathogen Biology, Guizhou Nursing Vocational College, Guiyang, Guizhou, 550000, People’s Republic of China, Email [email protected]: Clear cell renal cell carcinoma (ccRCC) is a relatively frequently diagnosed form of urological cancer that is highly malignant and associated with high rates of patient mortality. At present, there are few effective options for treating advanced cases of ccRCC, emphasizing the need to establish novel biomarkers and targets suitable for therapeutic intervention. SET domain bifurcated histone lysine methyltransferase 2 (SETDB2) belongs to the Su(var)3– 9 subfamily of methyltransferases and has been linked to various forms of cancer, but the role it plays in ccRCC remains to be fully established.Methods: Data on SETDB2 expression were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Functional enrichment analyses were then used to probe the putative role that SETDB2 plays in the onset of ccRCC. The Gene Set Cancer Analysis (GSCA) platform and molecular docking analysis were utilized to investigate the relationship between gene expression and drug sensitivity. In the end, the core target and the active molecule were both given the green light for a molecular docking investigation. Functional assays and Western blotting performed with ccRCC cell lines were employed for the validation of the findings from these predictive analyses.Results: SETDB2 downregulation was observed in ccRCC, and lower levels were found to linked with poor patient outcomes. Lower SETDB2 levels were associated with worse overall, progression-free, and disease-specific survival. In Functional enrichment analyses, SETDB2 was predicted to regulate key ccRCC development-associated pathways. SETDB2 levels were also significantly associated with cuproptosis induction in KIRC tissues, while in immune cell infiltration analyses, SETDB2 expression was linked with immune responses within the tumor microenvironment. Functional experiments conducted with ccRCC cell lines unveiled molecular mechanisms through which SETDB2 appears to be capable of inhibiting the development of ccRCC.Conclusion: Together, these analyses highlight the utility of SETDB2 as a prognostic biomarker in ccRCC. The interactions and associated pathways detected through these analyses provide unique insight into the potential functions of SETDB2 in this cancer type, providing an evidence base for future studies.Keywords: SETDB2, biomarkers, kidney renal clear cell carcinoma, prognosis, tumor-immune infiltration, cuproptosis