Transcription factor MAZ activates the transcription of hypomethylated TYMP in ccRCC

Abstract

Clear cell renal cell carcinoma (ccRCC) is a highly malignant tumor characterized by a significant propensity for recurrence and metastasis. DNA methylation has emerged as a critical epigenetic mechanism with substantial utility in cancer diagnosis. In this study, multi-omics data were utilized to investigate the target genes regulated by the transcription factor MYC-associated zinc finger protein (MAZ) in ccRCC, leading to the identification of thymidine phosphorylase (TYMP) as a gene with notably elevated expression in ccRCC. The interaction between MAZ and TYMP was confirmed through chromatin immunoprecipitation (ChIP) assays and bioinformatics analysis. It was found that the binding of MAZ to the TYMP promoter is associated with the methylation status of this promoter region. Furthermore, the methylation of the TYMP promoter appears to be correlated with both the clinicopathological stage and overall survival of ccRCC patients. Further exploration of genes within the “nucleotide metabolism” pathway, identified through Gene Ontology (GO) enrichment analysis, revealed that uridine phosphorylase 1 (UPP1) interacts with TYMP. Interestingly, UPP1 was also shown to be activated by MAZ, suggesting a coordinated regulatory mechanism. Based on these findings, we propose that the TYMP-UPP1 complex, co-regulated by MAZ, plays a pivotal role in nucleotide metabolism in ccRCC. These results suggest that TYMP may contribute to the pathophysiology of ccRCC and that promoter methylation offers potential as a prognostic indicator, providing novel insights into the molecular underpinnings of ccRCC and potential avenues for therapeutic intervention.