Language

English

Publication Date

2-6-2026

Journal

Scientific Reports

DOI

10.1038/s41598-026-38038-0

PMID

41652062

PMCID

PMC12932671

PubMedCentral® Posted Date

2-6-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Hepatoblastoma (HB) is the most common pediatric liver malignancy. However, its cellular origin and molecular drivers remain poorly defined. Using single-nuclear RNA sequencing (snRNA-seq), we identified a proliferative, hepatocyte-derived tumor cell population (cycling HepT) enriched for Enhancer of Zeste Homolog 2 (EZH2) expression, particularly in the aggressive embryonal subtype. Integrative genomic and transcriptomic profiling confirmed EZH2 overexpression. Disruption of the PRC2 complex was evident through mislocalization and reduced expression of SUZ12, a core component. EZH2 overexpression correlated with upregulation of mitotic regulators such as AURKB and Ki67 in human HB gene expression analysis as compared to background liver. Targeted sequencing identified variants of uncertain significance in EZH2 and SUZ12 in 11 of 11 patient tumors. Pharmacologic inhibition of EZH2 with EPZ-6438 reduced proliferation and sensitized HB cells to cisplatin through gene regulation, potentially modulating platinum accumulation both in vitro and in vivo. In summary, EZH2 promotes HB progression through epigenetic silencing and noncanonical signaling pathways. These findings support EZH2’s contribution to HB pathogenesis, therefore identifying it as a novel therapeutic target.

Keywords

Humans, Enhancer of Zeste Homolog 2 Protein, Hepatoblastoma, Liver Neoplasms, Gene Expression Regulation, Neoplastic, Animals, Cell Proliferation, Cell Line, Tumor, Polycomb Repressive Complex 2, Epigenesis, Genetic, Cisplatin, Female, Neoplasm Proteins, Transcription Factors, Aurora Kinase B, EZH2, Hepatoblastoma, Epigenetics, Mitotic regulation, Therapeutic target, Cancer, Cell biology, Genetics, Molecular biology, Oncology

Published Open-Access

yes

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