Disulfidptosis-related subtype and prognostic signature in prostate cancer.

Abstract

Background: Disulfidptosis refers to cell death caused by the accumulation and bonding of disulfide in the cytoskeleton protein of SLC7A11-high level cells under glucose deprivation. However, the role of disulfidptosis-related genes (DRGs) in prostate cancer (PCa) classification and regulation of the tumor microenvironment remains unclear.

Methods: Firstly, we analyzed the expression and mutation landscape of DRGs in PCa. We observed the expression levels of SLC7A11 in PCa cells through in vitro experiments and assessed the inhibitory effect of the glucose transporter inhibitor BAY-876 on SLC7A11-high cells using CCK-8 assay. Subsequently, we performed unsupervised clustering of the PCa population and analyzed the differentially expressed genes (DEGs) between clusters. Using machine learning techniques to select a minimal gene set and developed disulfidoptosis-related risk signatures for PCa. We analyzed the tumor immune microenvironment and the sensitivity to immunotherapy in different risk groups. Finally, we validated the accuracy of the prognostic signatures genes using single-cell sequencing, qPCR, and western blot.

Results: Although SLC7A11 can increase the migration ability of tumor cells, BAY-876 effectively suppressed the viability of prostate cancer cells, particularly those with high SLC7A11 expression. Based on the DRGs, PCa patients were categorized into two clusters (A and B). The risk label, consisting of a minimal gene set derived from DEGs, included four genes. The expression levels of these genes in PCa were initially validated through in vitro experiments, and the accuracy of the risk label was confirmed in an external dataset. Cluster-B exhibited higher expression levels of DRG, representing lower risk, better prognosis, higher immune cell infiltration, and greater sensitivity to immune checkpoint blockade, whereas Cluster A showed the opposite results. These findings suggest that DRGs may serve as targets for PCa classification and treatment. Additionally, we constructed a nomogram that incorporates DRGs and clinical pathological features, providing clinicians with a quantitative method to assess the prognosis of PCa patients.

Conclusion: This study analyzed the potential connection between disulfidptosis and PCa, and established a prognostic model related to disulfidptosis, which holds promise as a valuable tool for the management and treatment of PCa patients.