Epigenetic Regulation and Therapeutic Potential of Gasdermin Genes in Colorectal Adenocarcinoma

Year 2023, Volume: 13 Issue: 3, 218 - 256, 28.12.2023

Feyzanur Yıldırımtepe Çaldıran , Rümeysa Şenyuva , Ercan Çaçan

https://doi.org/10.26650/experimed.1374173

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.

Keywords

Colorectal adenocarcinoma, gasdermin C, gasdermin D, epigenetic regulation, vorinostat, 5-azacytidine

Ethical Statement

Not applicable

Supporting Institution

Tubitak

Project Number

TUBITAK 2209-A (1919B012209018)

Thanks

The authors would like to thank to Caglar Berkel for his assistance.

References

• 1. Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol 2019; 14(2): 89-103. google scholar
• 2. Caldiran FY, Cacan E. RGS10 suppression by DNA methylation is associated with low survival rates in colorectal carcinoma. Pathol Res Pract 2022; 236: 154007. google scholar
• 3. Bardhan K, Liu K. Epigenetics and colorectal cancer pathogenesis. Cancers (Basel) 2013; 5(2): 676-713. google scholar
• 4. Ashktorab H, Brim H. DNA methylation and colorectal cancer. Curr Colorectal Cancer Rep 2014; 10(4): 425-30. google scholar
• 5. Park J, Lee K, Kim K, Yi SJ. The role of histone modifications: from neurodevelopment to neurodiseases. Signal Transduct Target Ther 2022; 7(1): 217. google scholar
• 6. Orzolek I, Sobieraj J, Domagala-Kulawik J. Estrogens, cancer and immunity. Cancers 2022; 14(9); 2265. google scholar
• 7. Bozovic A, Mandusic V, Todorovic L, Krajnovic M. Estrogen Receptor Beta: The promising biomarker and potential target in metastases. Int J Mol Sci 2021; 22(4): 1656. google scholar
• 8. Berkel C, Cacan E. Estrogen- and estrogen receptor (ER)-mediated cisplatin chemoresistance in cancer. Life Sci 2021; 286:20029. google scholar
• 9. Fortress AM, Frick KM. Epigenetic regulation of estrogen-dependent memory. Front Neuroendocrinol 2014; 35(4): 530-49. google scholar
• 10. El-Gamal R, Abdelrahim M, El-Sherbiny M, Enan ET, El-Nablaway M. Gasdermin D: A potential mediator and prognostic marker of bladder cancer. Front Mol Biosci 2022; 9: 972087. google scholar
• 11. Tanaka S, Orita H, Kataoka T, Miyazaki M, Saeki H, Wada R, et al. Gasdermin D represses inflammation-induced colon cancer development by regulating apoptosis. Carcinogenesis 2023; 44(4): 341-9. google scholar
• 12. Yang X, Tang Z. Role of gasdermin family proteins in cancers. Int J Oncol 2023; 63(3): 100. google scholar
• 13. Slaufova M, Karakaya T, Di Filippo M, Hennig P, Beer HD. The gasdermins: a pore-forming protein family expressed in the epidermis. Front Immunol 2023; 14: 1254150. google scholar
• 14. Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res 2020; 48(W1): W509-14. google scholar
• 15. Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK, et al. UALCAN: A Portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 2017; 19(8): 649-58. google scholar
• 16. Thul PJ, Lindskog C. The human protein atlas: a spatial map of the human proteome. Protein Sci 2018; 27(1): 233-44. google scholar
• 17. Xiong Z, Yang F, Li M, Ma Y, Zhao W, Wang G, et al. EWAS Open Platform: integrated data, knowledge and toolkit for epigenome-wide association study. Nucleic Acids Res 2022; 50(D1): D1004-9. google scholar
• 18. D^ez-Villanueva A, Mallona I, Peinado MA (). Wanderer, an interactive viewer to explore DNA methylation and gene expression data in human cancer. Epigenetics Chromatin 2015; 8: 22. google scholar
• 19. Liu CJ, Hu FF, Xie GY, Miao YR, Li XW, Zeng Y, et al. GSCA: an integrated platform for gene set cancer analysis at genomic, pharmacogenomic and immunogenomic levels. Brief Bioinform 2023; 24(1): bbac558. google scholar
• 20. Fekete JT, Gyorffy B. ROCplot.org: validating predictive biomarkers of chemotherapy/hormonal therapy/anti-HER2 therapy using transcriptomic data of 3,104 breast cancer patients. Int J Cancer 2019; 145(11): 3140-51. google scholar
• 21. Zou J, Zheng Y, Huang Y, Tang D, Kang R, Chen R. The versatile gasdermin family: their function and roles in diseases. Front Immunol 2021; 12: 751533. google scholar
• 22. Feng S, Fox D, Man SM Mechanisms of gasdermin family members in inflammasome signaling and cell death J Mol Biol 2018; 430(18 Pt B): 3068-3080 google scholar
• 23. Miguchi M, Hinoi T, Shimomura M, Adachi T, Saito Y, Niitsu H, et al Gasdermin C is upregulated by inactivation of transforming growth factor 0 receptor type II in the presence of mutated Apc, promoting colorectal cancer proliferation PLoS One 2016; 11(11): e0166422 google scholar
• 24. Wang J, Kang Y, Li Y, Sun L, Zhang J, Qian S, et al Gasdermin D in different subcellular locations predicts diverse progression, ımmune microenvironment and prognosis in colorectal cancer J Inflamm Res 2021; 14: 6223-35 google scholar
• 25. Berkel C, Cacan E Differential expression and copy number variation of gasdermin (GSDM) family members, pore-forming proteins in pyroptosis, in normal and malignant serous ovarian tissue Inflammation 2021; 44(6): 2203-16 google scholar
• 26. Li F, Xia Q, Ren L, Nie Y, Ren H, Guo X, et al GSDME Increases chemotherapeutic drug sensitivity by inducing pyroptosis in retinoblastoma cells Oxid Med Cell Longev 2022; 2022: 2371807 google scholar
• 27. Kim MS, Chang X, Yamashita K, Nagpal JK, Baek JH, Wu G, et al Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma Oncogene 2008; 27(25): 3624-34 google scholar
• 28. Wang YY, Shi LY, Xu MH, Jing Y, Sun CC, Yang JH, et al A pan-cancer analysis of the expression of gasdermin genes in tumors and their relationship with the immune microenvironment Transl Cancer Res 2021; 10(9): 4125-47 google scholar
• 29. Niu Q, Liu Y, Zheng Y, Tang Z, Qian Y, Qi R, et al Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics Acta Pharm Sin B 2022; 12(12): 4458-71 google scholar
• 30. Zhao S, Guo J, Zhao Y, Fei C, Zheng Q, Li X, et al Chidamide, a novel histone deacetylase inhibitor, inhibits the viability of MDS and AML cells by suppressing JAK2/STAT3 signaling Am J Transl Res 2016; 8(7): 3169-78 google scholar