Abstract:

Objective: Colorectal adenocarcinoma (COAD) is a complex and lethal cancer characterized by genetic mutations and epigenetic alterations. Gasdermin proteins, such as gasdermin C (GSDMC) and gasdermin D (GSDMD), play crucial roles in pyroptotic cell death, presenting these proteins as potential targets for diagnosis markers and therapy across various cancers, including COAD. Our study investigated the epigenetic regulation of GSDMC and GSDMD in COAD using bioinformatics and in vitro experiments. Materials and Methods: This study examined the expression and epigenetic control of pyroptosis-related proteins in COAD using bioinformatics tools and databases such as Timer2.0, UALCAN, EWAS Open Platform, Gene Set Cancer Analysis (GSCA), Receiver Operating Characteristic (ROC) plotter, and WANDERER. To investigate target gene expression, HTC-116 and SW620 cell lines were subjected to treatments with estrogen, a DNA methylation inhibitor (5-azacytidine), and a histone deacetylase inhibitor (vorinostat). Results: The results showed that the expression of GSDMC and GSDMD varies based on the subtype of COAD. We established that these genes are regulated through DNA hypermethylation in the cg05316065 island for GSDMC and the cg10810860 island for GSDMD. Additionally, the identification of 5-fluorouracil, oxaliplatin, fluoropyrimidine monotherapy, and capecitabine as predictive biomarkers for GSDMC and GSDMD genes underscores the potential clinical utility in cancer therapy. Our results showed that a combined treatment involving 5-azacytidine, vorinostat, and estrogen increases the expression of these genes, potentially guiding cells toward pyroptosis. Conclusions: This comprehensive analysis reveals the complex roles of GSDMC and GSDMD genes in cancer progression, showcasing their susceptibility to epigenetic regulation and impact on chemotherapy responses. These findings offer crucial insights into their significance as potential targets for diagnosis and therapy in cancer, thereby paving the way for personalized treatment strategies.

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