Zeng Liang, Xu Hui, Li Meng, Qin Liang-Jun, Chen Kai, Wang Feng-Hua, Li Xiaomin, Yang Tianyou, Miao Lei, Wang Hai-Yun
Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children's Medical Center for South Central Region, Guangzhou, China.
Department of Paediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children's Medical Center for South Central Region, Guangzhou, China.
Cell Death Dis. 2025 Aug 12;16(1):613. doi: 10.1038/s41419-025-07932-2.
Neuroblastoma is the most common extracranial malignancy in children, and patients who develop recurrent or metastatic disease are likely to have a much poorer survival prognosis. Herein, by applying random forest and XGBoost machine-learning techniques, we identified interferon regulatory factor (IRF) 6 as the most crucial gene associated with neuroblastoma patient survival. Low IRF6 expression was further determined to be associated with dismal survival in neuroblastoma patients. IRF6 overexpression inhibited cell proliferation in vitro and in vivo and even weakened glycolytic metabolism and increased maximal respiration in SK-N-BE2 and CHP-212 cells. Mechanistically, RNA sequencing, ChIP, and dual-luciferase reporter assays revealed that IRF6 inhibited PGM1 expression by decreasing the transcriptional activity of promoter 3 of PGM1, and PGM1 overexpression may reverse the inhibitory effects of IRF6 on cell proliferation and glycolysis. Additionally, IRF6 expression was diminished in neuroblastoma due to E3 ligase TRIM59-mediated polyubiquitination, and may reverse the promoting effect of TRIM59 overexpression on cell proliferation and glycolysis. Our work thus provides mechanistic insight into the control of glycolysis-mediated disease progression and opens new avenues for developing therapeutic strategies in neuroblastoma.
神经母细胞瘤是儿童最常见的颅外恶性肿瘤，出现复发或转移性疾病的患者生存预后可能要差得多。在此，通过应用随机森林和XGBoost机器学习技术，我们确定干扰素调节因子（IRF）6是与神经母细胞瘤患者生存相关的最关键基因。进一步确定IRF6低表达与神经母细胞瘤患者的不良生存相关。IRF6过表达在体外和体内均抑制细胞增殖，甚至削弱SK-N-BE2和CHP-212细胞的糖酵解代谢并增加最大呼吸。机制上，RNA测序、染色质免疫沉淀和双荧光素酶报告基因检测表明，IRF6通过降低PGM1启动子3的转录活性来抑制PGM1表达，而PGM1过表达可能逆转IRF6对细胞增殖和糖酵解的抑制作用。此外，由于E3连接酶TRIM59介导的多聚泛素化，神经母细胞瘤中IRF6表达降低，并且可能逆转TRIM59过表达对细胞增殖和糖酵解的促进作用。因此，我们的工作为糖酵解介导的疾病进展控制提供了机制性见解，并为开发神经母细胞瘤治疗策略开辟了新途径。
