Degradation of IRF6 by TRIM59 in tumor cells triggers PGM1-mediated glycolysis to regulate cell proliferation in neuroblastoma.

Journal: Cell death & disease
Published Date: Aug 12, 2025

Abstract

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.

Authors

  • Liang Zeng
    Departement of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha 410013, China.
  • Hui Xu
    No 202 Hospital of People's Liberation Army, Liaoning 110003, China.
  • Meng Li
    Co-Innovation Center for the Sustainable Forestry in Southern China; Cerasus Research Center; College of Biology and the Environment, Nanjing Forestry University, Nanjing, China.
  • Liang-Jun Qin
    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.
  • Kai Chen
    Department of Critical Care Medicine, Fujian Provincial Key Laboratory of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fuzhou, Fujian, China.
  • Feng-Hua Wang
    Department of Thoracic 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.
  • Xiaomin Li
    Medical and Hygienic Materials Research Institute, SINOPEC (Beijing) Research Institute of Chemical Industry Co., Ltd., Beijing 100013, China.
  • Tianyou Yang
    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.
  • Lei Miao
    School of Computer Science and Engineering, Key Laboratory of Computer Network and Information Integration, Ministry of Education, Southeast University, Nanjing 210096, China. Electronic address: miaolei@seu.edu.cn.
  • Hai-Yun Wang
    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. wanghy29@mail3.sysu.edu.cn.

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