通过下调脂肪合成酶FASN和ERK信号传导，m6A修饰介导的OGDHL在ccRCC中发挥抑制肿瘤的作用。
The m6A modification-mediated OGDHL exerts a tumor suppressor role in ccRCC by downregulating FASN to inhibit lipid synthesis and ERK signaling.
发表日期：2023 Aug 25
作者：
Jian Shi, Daojia Miao, Qingyang Lv, Keshan Wang, Qi Wang, Huageng Liang, Hongmei Yang, Zhiyong Xiong, Xiaoping Zhang
来源：
Cell Death & Disease
摘要：
代谢重编程是癌症的一个特征，脂质代谢作为代谢重编程的一个关键方面对于透明细胞肾细胞癌（ccRCC）的进展已经被确立。然而，代谢异常与ccRCC进展之间的调控机制仍不清楚。因此，本研究旨在确定ccRCC代谢重编程的关键调控因子，并为ccRCC患者提供潜在的治疗靶点。使用生物信息学分析筛选了ccRCC中的潜在代谢调控因子。使用公共数据库和患者样本研究了ccRCC中羰基戊二酸脱氢酶样蛋白（OGDHL）的异常表达。通过体外和体内功能实验评估了OGDHL在ccRCC生长和转移中的作用。通过荧光素酶报告载体实验、染色质免疫沉淀、RNA甲基化免疫沉淀和突变研究获得了机制洞察。OGDHL的mRNA和蛋白水平在ccRCC组织中显著下调。上调OGDHL表达有效抑制了ccRCC的体外和体内生长和转移。此外，FTO介导的OGDHL m6A去甲基化抑制了ccRCC中OGDHL的表达。在机制上，OGDHL水平低下通过抑制泛素化水平促进了TFAP2A的表达，TFAP2A然后结合FASN启动子区域，并转录激活FASN表达，从而促进脂质积累和ERK通路激活。我们的研究结果显示OGDHL对ccRCC进展的影响，并突显了FTO/OGDHL/TFAP2A/FASN轴在调控ccRCC脂质代谢和进展中的作用，为ccRCC治疗提供了新的靶点。© 2023. 作者。
Metabolic reprogramming is a hallmark of cancer, and the impact of lipid metabolism as a crucial aspect of metabolic reprogramming on clear cell renal cell carcinoma (ccRCC) progression has been established. However, the regulatory mechanisms underlying the relationship between metabolic abnormalities and ccRCC progression remain unclear. Therefore, this study aimed to identify key regulatory factors of metabolic reprogramming in ccRCC and provide potential therapeutic targets for ccRCC patients. Potential metabolic regulatory factors in ccRCC were screened using bioinformatics analysis. Public databases and patient samples were used to investigate the aberrant expression of Oxoglutarate dehydrogenase-like (OGDHL) in ccRCC. The function of OGDHL in ccRCC growth and metastasis was evaluated through in vitro and in vivo functional experiments. Mechanistic insights were obtained through luciferase reporter assays, chromatin immunoprecipitation, RNA methylation immunoprecipitation, and mutagenesis studies. OGDHL mRNA and protein levels were significantly downregulated in ccRCC tissues. Upregulation of OGDHL expression effectively inhibited ccRCC growth and metastasis both in vitro and in vivo. Furthermore, FTO-mediated OGDHL m6A demethylation suppressed its expression in ccRCC. Mechanistically, low levels of OGDHL promoted TFAP2A expression by inhibiting ubiquitination levels, which then bound to the FASN promoter region and transcriptionally activated FASN expression, thereby promoting lipid accumulation and ERK pathway activation. Our findings demonstrate the impact of OGDHL on ccRCC progression and highlight the role of the FTO/OGDHL/TFAP2A/FASN axis in regulating ccRCC lipid metabolism and progression, providing new targets for ccRCC therapy.© 2023. The Author(s).