FOXM1 Targets TRIM59 to Activate Wnt/β-Catenin in Tumor Stemness and Hepatoblastoma Metastasis
- 1Department of Pediatric Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, China
- 2Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, China
Abstract
Hepatoblastoma is the most common liver malignancy in children. Approximately 20% of patients present metastasis at diagnosis and have a dismal prognosis. However, the molecular mechanisms and targeted therapeutic strategies remain limited. Integrated analysis of GSE151347, GSE133039, GSE131329 and GSE75271 datasets, incorporating the mRNA expression-based stemness index, weighted gene co-expression network analysis, ChEA3 and TRRUST databases, receiver operating characteristic (ROC) curve and differential expression analysis, identified forkhead box protein M1 (FOXM1) as a key transcription factor significantly correlated with metastatic hepatoblastoma and poor clinical outcomes. In HuH6 and HepG2 cells, FOXM1 promoted stem cell-like phenotype, migration, invasion and epithelial–mesenchymal transition. In vivo, FOXM1 promoted tumor growth in a subcutaneous xenograft model and lung colonization in a tail-vein injection model. The CUT&Tag sequencing revealed that FOXM1 occupied the tripartite motif containing 59 (TRIM59) promoter, and dual-luciferase reporter assays confirmed that FOXM1 transcriptionally activated TRIM59. Furthermore, FOXM1 gain- and loss-of-function were accompanied by changes in axis inhibition protein 1 (AXIN1) protein levels, β-catenin levels, and β-catenin nuclear translocation, potentially contributing to the regulation of Wnt/β-catenin signaling. Finally, TRIM59 knockdown successfully rescued FOXM1-driven malignant phenotypes. This study identifies a novel FOXM1/TRIM59/Wnt signaling axis that drives hepatoblastoma metastasis, highlighting FOXM1 and TRIM59 as promising therapeutic targets for high-risk patients.
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BibTeX
@article{yan2026foxm1,
title = {{FOXM1 Targets TRIM59 to Activate Wnt/β-Catenin in Tumor Stemness and Hepatoblastoma Metastasis}},
author = {Hanlei Yan and Wei Liu and Wanying Jia and Jingjing Huang and Wenyao Xu and Zihao Fu and Baijun Zheng and Hui Yu and Xinlin Chen and Ya Gao and Donghao Tian},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219843},
url = {https://www.mdpi.com/1422-0067/27/21/9843},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - FOXM1 Targets TRIM59 to Activate Wnt/β-Catenin in Tumor Stemness and Hepatoblastoma Metastasis
AU - Hanlei Yan
AU - Wei Liu
AU - Wanying Jia
AU - Jingjing Huang
AU - Wenyao Xu
AU - Zihao Fu
AU - Baijun Zheng
AU - Hui Yu
AU - Xinlin Chen
AU - Ya Gao
AU - Donghao Tian
PY - 2026
DA - 2026/11/03
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219843
UR - https://www.mdpi.com/1422-0067/27/21/9843
AB - Hepatoblastoma is the most common liver malignancy in children. Approximately 20% of patients present metastasis at diagnosis and have a dismal prognosis. However, the molecular mechanisms and targeted therapeutic strategies remain limited. Integrated analysis of GSE151347, GSE133039, GSE131329 and GSE75271 datasets, incorporating the mRNA expression-based stemness index, weighted gene co-expression network analysis, ChEA3 and TRRUST databases, receiver operating characteristic (ROC) curve and differential expression analysis, identified forkhead box protein M1 (FOXM1) as a key transcription factor significantly correlated with metastatic hepatoblastoma and poor clinical outcomes. In HuH6 and HepG2 cells, FOXM1 promoted stem cell-like phenotype, migration, invasion and epithelial–mesenchymal transition. In vivo, FOXM1 promoted tumor growth in a subcutaneous xenograft model and lung colonization in a tail-vein injection model. The CUT&Tag sequencing revealed that FOXM1 occupied the tripartite motif containing 59 (TRIM59) promoter, and dual-luciferase reporter assays confirmed that FOXM1 transcriptionally activated TRIM59. Furthermore, FOXM1 gain- and loss-of-function were accompanied by changes in axis inhibition protein 1 (AXIN1) protein levels, β-catenin levels, and β-catenin nuclear translocation, potentially contributing to the regulation of Wnt/β-catenin signaling. Finally, TRIM59 knockdown successfully rescued FOXM1-driven malignant phenotypes. This study identifies a novel FOXM1/TRIM59/Wnt signaling axis that drives hepatoblastoma metastasis, highlighting FOXM1 and TRIM59 as promising therapeutic targets for high-risk patients.
SN - 1422-0067
ER -