# Investigating the oncogenic role of aberrant EZH2 in hepatoblastoma

## TL;DR

This study explores how abnormal EZH2 activity contributes to liver cancer in children and suggests it could be a new treatment target.

## Contribution

The study identifies EZH2 as a novel therapeutic target in hepatoblastoma through its epigenetic and signaling roles.

## Key findings

- EZH2 overexpression is linked to aggressive hepatoblastoma subtypes and mitotic regulator upregulation.
- Pharmacologic inhibition of EZH2 reduces tumor proliferation and increases cisplatin sensitivity in hepatoblastoma cells.
- Genomic analysis reveals EZH2 and SUZ12 variants in all 11 patient tumors, indicating potential functional relevance.

## 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.

The online version contains supplementary material available at 10.1038/s41598-026-38038-0.