CX3CL1 promotes cell sensitivity to ferroptosis and is associated with the tumor microenvironment in clear cell renal cell carcinoma

Abstract

Background An increasing number of studies have demonstrated that CX3CL1 is involved in the development of tumors and may thus be considered a new potential therapeutic target for them. However, the function of CX3CL1 in clear cell renal cell carcinoma (ccRCC) remains poorly defined. Methods The pan-cancer expression pattern and prognostic value of CX3CL1 were evaluated in this study. Moreover, the relationship of CX3CL1 expression with the tumor microenvironment, especially the tumor immune microenvironment, was analyzed. Our analyses employed public repository data. Additionally, we generated stable CX3CL1-overexpressing 786-O cells to determine the role of CX3CL1 in vitro via cell viability and transwell assays. A xenograft tumor model was used to determine the role of CX3CL1 in vivo. The association between CX3CL1 and ferroptosis sensitivity of tumor cells was assessed using Ferrostatin-1. Results Our findings indicated the involvement of CX3CL1 in the occurrence and development of ccRCC by acting as a tumor suppressor. We also found that ccRCC patients with high CX3CL1 expression showed better clinical outcomes than those with low CX3CL1 expression. The findings of our epigenetic study suggested that the expression of CX3CL1 in ccRCC is correlated with its DNA methylation level. Furthermore, the CX3CL1 expression level was closely related to the infiltration level of CD8+ T cells into the tumor microenvironment (TME). CX3CL1 showed different predictive values in different immunotherapy cohorts. Finally, CX3CL1 overexpression inhibited tumor cell proliferation and metastasis and promoted tumor ferroptosis sensitivity in ccRCC. Conclusions This study revealed the role of CX3CL1 as a tumor suppressor in ccRCC. Our findings indicated that CX3CL1 plays a crucial role in regulating the ccRCC TME and is a potential predictor of immunotherapy outcomes in ccRCC. We also found that CX3CL1 can promote ferroptosis sensitivity in ccRCC cells.

Novel Insight into Ferroptosis in Kidney Diseases

“…Some studies have indicated that reduced ACADSB expression predicts poor prognosis in ccRCC [88]. miRNA-4735-3p targeted SLC40A1 to facilitate ferroptosis in ccRCC [89], and CX3CL1 enhanced cell susceptibility to ferroptosis and was related to the tumor microenvironment [90]. Ferroptosis was weakened by succinate dehydrogenase’s functional deficit, which encouraged tumorigenesis and the growth of ccRCC [91].…”

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

“… 193 ccRCC Methylation β-OHB - CX3CL1 overexpression inhibited tumor cell proliferation and metastasis and promoted tumor ferroptosis sensitivity in ccRCC.The expression of CX3CL1 in ccRCC is correlated with its DNA methylation level. 195 ccRCC Methylation SDH - Increased methylation and high SDH promoter mutation rates lead to deficiency of SDH, thereby promoting tumorigenesis through weakening of ferroptosis. 196 ALL Methylation FSP1 - The promoter of the gene coding for FSP1 is hypermethylated in ALL, silencing the expression of FSP1 and creating a selective dependency on GSH-centered anti-ferroptosis defenses.…”

“…The expression of CX3CL1 is associated with its DNA methylation level in ccRCC. 195 Decreased expression of succinate dehydrogenase (SDH), which is responsible for oxidative phosphorylation (OXPHOS) and flux through the tricarboxylic acid (TCA) cycle, is correlated with ccRCC progression. SDH deficiency enhances tumorigenesis by inhibiting ferroptosis in ccRCC cells.…”

Effects of DNA, RNA, and Protein Methylation on the Regulation of Ferroptosis

“…DNA methylation of the Fsp1 promoter prevented NRF2 from binding to its promoter and inhibited transcription [20,123]. In addition, DNA methylation of many other genes has been reported to contribute to ferroptosis regulation [98,[124][125][126][127][128]. For example, embryonic lethal-abnormal vision-like protein 1 (ELAVL1), a well characterized RNA-binding protein that promotes target mRNA stability, has been found to bind to the 3'UTR of DNMT3B mRNA, thereby facilitating its expression during cerebral ischemia/ reperfusion (I/R) injury.…”