2. Academic Validation
  3. TCF3 activates super-enhancer-driven TRIB2 overexpression to suppress ferroptosis and promote hepatoblastoma proliferation

TCF3 activates super-enhancer-driven TRIB2 overexpression to suppress ferroptosis and promote hepatoblastoma proliferation

  • J Exp Clin Cancer Res. 2025 Dec 29;44(1):329. doi: 10.1186/s13046-025-03587-1.
Han Wu # 1,  Guoqing Zhu # 1,  Qianshu Zhu # 2,  Ji Ma 1,  Siwei Mao 1,  Miao Ding 1,  Jiabei Zhu 1,  Xiaochen Tang 1,  Zhixuan Bian 1,  Yuhua Shan 3,  Song Gu 3,  Fenyong Sun 4,  Cizhong Jiang 5,  Qiuhui Pan 6 7 8 9
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Dongfang Road No.1678, Pudong New District, Shanghai, 200127, China.
  • 2 Chongqing Key Laboratory of Human Embryo Engineering and Precision Medicine, NHC Key Laboratory of Birth Defects and Reproductive Health, Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of Oncology Surgery, International Diagnosis and Treatment (Special Consultation) Department, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Department of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Middle Yanchang Road No.301, Jing'an District, Shanghai, 200072, China. [email protected].
  • 5 Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Siping Road No.1239, Yangpu District, Shanghai, 200092, China. [email protected].
  • 6 Department of Clinical Laboratory, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Dongfang Road No.1678, Pudong New District, Shanghai, 200127, China. [email protected].
  • 7 Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8 Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, China. [email protected].
  • 9 Hainan Branch, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya, Hainan, China. [email protected].
  • # Contributed equally.
PMID: 41462308 DOI: 10.1186/s13046-025-03587-1
Abstract

Background: Hepatoblastoma (HB) is the most common pediatric liver malignancy with an increasing incidence. However, the functional roles of 3D chromatin organization, epigenetic regulatory factors, and transcriptional reprogramming in HB pathogenesis remain poorly understood.

Methods: ​Integrated multi-omics analyses of HB and matched non-tumor tissues were performed, including Hi-C, H3K27ac CUT&Tag, ATAC-seq, and RNA-seq, to construct high-resolution 3D epigenomic maps and identify genes interacting with HB-specific super-enhancers (SEs). Functional assays of identified targets were conducted in cell lines and animal models. The regulatory mechanisms of SEs and upstream transcription factors (TFs) were investigated using CRISPRi-dCas9, 3C-qPCR, ChIP-qPCR, and luciferase reporter assays.

Results: Comprehensive analysis identified TRIB2 as an HB-specific SE-associated oncogene. Functionally, TRIB2 promoted cell proliferation and accelerated tumor growth both in vitro and in vivo. Patients with high TRIB2 expression exhibited advanced PRETEXT stage and metastasis. Mechanistically, TCF3 directly bound to both the TRIB2-SE and its promoter, promoting TRIB2 overexpression. Moreover, TRIB2 conferred resistance to Ferroptosis by disrupting KEAP1-mediated ubiquitination of NRF2, thereby stabilizing NRF2 protein and enhancing antioxidant responses. The TCF3-TRIB2-NRF2 axis showed significant co-expression in HB tissues, effectively distinguished HB from normal liver tissues, and was associated with poorer overall survival.

Conclusions: Our findings reveal that TCF3 and SE mediate TRIB2 overexpression to inhibit Ferroptosis via the Keap1-Nrf2 pathway and drive HB pathogenesis, providing potential diagnostic and prognostic markers for HB.

Keywords

Epigenetics; Hepatoblastoma; Hi-C; KEAP1; Multi-omics; NRF2; Reactive oxygen species; Super-enhancer; TRIB2.

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