Exploring Chromatin Regulatory Factor Genes as Novel Biomarkers and Immunotherapy Targets through Multi-Omics Analysis in Kidney Renal Clear Cell Carcinoma to Uncover Tumor Heterogeneity

Abstract Background: Kidney Renal Clear Cell Carcinoma (KIRC) is the primary subtype of renal cell carcinoma, accounting for a significant proportion of cases, ranging from 75% to 80%, with a cancer-specific mortality rate as high as 24%. Despite significant advancements in treatment modalities, KIRC exhibits notable resistance to conventional therapeutic approaches, underscoring the imperative need for pioneering targeted immunotherapeutic strategies. Within this framework, Chromatin Regulators (CRs) - pivotal proteins governing gene expression and orchestrating critical biological processes - have been recognized as key players in the initiation and progression of KIRC. In this study, we employed multi-omics approach to unveil the impact of genes closely associated with CRs on the prognosis of KIRC. Methods: Utilizing the TCGA-KIRC dataset, we constructed and validated a prognostic model using LASSO Cox regression, emphasizing genes that significantly influence KIRC prognosis. Furthermore, our study investigated interactions among gene characteristics, clinical parameters, tumor microenvironment, targeted immunotherapy, and drug responsiveness. Experimental validation, encompassing cell culture, transient transfection, qPCR, Transwell assays, and more, substantiated the outstanding predictive capability of the BRD9 gene. Results: Through an analysis of relevant studies, we have identified the risk score of Chromatin Regulators (CRs) as an independent determinant of KIRC prognosis. Subsequently, we developed a predictive Nomogram model that combines clinical attributes and corresponding risk assessment. Finally, we compared and analyzed the expression levels of BRD9 in normal and tumor tissues using techniques such as polymerase chain reaction (PCR). It is noteworthy that BRD9 exhibits a significant increase in expression within renal clear cell carcinoma cells. In summary, these findings reveal the oncogenic role of BRD9, with its upregulated expression playing a pivotal role in promoting the proliferation, invasion, and migration of renal clear cell carcinoma cells. Consequently, targeted immunotherapy for renal clear cell carcinoma can be tailored based on this gene. Conclusion: Within the scope of this study, we have introduced a novel KIRC prognostic framework based on multi-omics approaches, seamlessly integrating Chromatin Regulators. This innovative model holds the potential to enhance the accuracy of prognosis prediction for KIRC patients, laying a solid foundation for the development of targeted immunotherapeutic approaches for KIRC patients.