Dong Yihan, Liu Xinyu, Li Jiaxin, Lin Tianyu, Wang Rui, Jiang Huamao, Wang Yong, Yue Dan
School of Medical Technology, Tianjin Medical University, Tianjin, 300203, China.
Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
Funct Integr Genomics. 2025 Jan 11;25(1):12. doi: 10.1007/s10142-024-01510-z.
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.
透明细胞肾细胞癌（ccRCC）是一种高度恶性的肿瘤，其特点是具有显著的复发和转移倾向。DNA甲基化已成为一种关键的表观遗传机制，在癌症诊断中具有重要作用。在本研究中，利用多组学数据研究了转录因子MYC相关锌指蛋白（MAZ）在ccRCC中调控的靶基因，从而鉴定出胸苷磷酸化酶（TYMP）是一种在ccRCC中表达显著升高的基因。通过染色质免疫沉淀（ChIP）分析和生物信息学分析证实了MAZ与TYMP之间的相互作用。发现MAZ与TYMP启动子的结合与该启动子区域的甲基化状态有关。此外，TYMP启动子的甲基化似乎与ccRCC患者的临床病理分期和总生存期均相关。通过基因本体论（GO）富集分析鉴定出的“核苷酸代谢”途径中的基因进一步探索发现，尿苷磷酸化酶1（UPP1）与TYMP相互作用。有趣的是，UPP1也被证明受MAZ激活，提示存在一种协同调控机制。基于这些发现，我们提出由MAZ共同调控的TYMP-UPP1复合物在ccRCC的核苷酸代谢中起关键作用。这些结果表明TYMP可能参与ccRCC的病理生理过程，且启动子甲基化有望作为一种预后指标，为ccRCC的分子基础及潜在治疗干预途径提供了新的见解。
