Interplay between RNA Methylation Eraser FTO and Writer METTL3 in Renal Clear Cell Carcinoma Patient Survival

Abstract

Background: m6A-methyltransferase METTL3 and demethylase FTO regulate gene expression by dynamically modifying RNA methylation. However, their clinical relevance in renal Clear Cell Carcinoma (CCRCC) has not been well elucidated. Objective: This study aims to investigate prognostic values of FTO and METTL3 mRNA and DNA methylation, their differential expression and associations with chemokines and inflammation-related genes in CCRCC. Methods: Kaplan-Meier survival curves and multivariate cox regression were performed for survival analyses, and random-effects meta-analysis was conducted for differential expression of FTO and METTL3 in CCRCC. Results: A significantly negative correlation was observed between mRNA and DNA methylation for both FTO and METTL3. Survival analysis showed a superior survival in patients with either high FTO mRNA or low DNA methylation, or low METTL3 mRNA or high DNA methylation. The adjusted hazard ratios were 0.67 (95% CI: 0.49-0.91, p = 0.01) for high vs. low FTO mRNA, 2.17 (1.38-3.42, p = 0.0008) for high vs. low FTO DNA methylation, 1.97 (1.45-2.68, p<0.0001) for high vs. low METTL3 mRNA, and 0.49 (0.31-0.79, p = 0.003) for high vs. low METTL3 DNA methylation, respectively. There was a significant interaction between FTO and METTL3 mRNA levels (p = 0.024). Upregulation of FTO and METTL3 with 1.64 folds (95% CI: 1.43-1.89) and 1.17 folds (1.02-1.35), respectively, was observed in CCRCC vs. normal kidney tissues. FTO and METTL3 mRNA showed opposite expressions of CD8+ T cell migration-related chemokines. Conclusion: Dysregulated FTO and METTL3 may be involved in the disease development and progression, affecting immune response in CCRCC. FTO and METTL3 expression and DNA methylation are potential prognostic markers of CCRCC.