Investigating the oncogenic role of aberrant EZH2 in hepatoblastoma

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.

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Publication Details

Journal
Scientific Reports
Published
2026-02-06
DOI
https://doi.org/10.1038/s41598-026-38038-0
Primary Topic
Epigenetics and DNA Methylation
Type
article
Field-Weighted Citation Impact
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article

Investigating the oncogenic role of aberrant EZH2 in hepatoblastoma

Lara Berklite, Priyanka Rao, Emily Schepers, Andrew Badachhape et al.
Scientific Reports
Epigenetics and DNA Methylation
article

Investigating the oncogenic role of aberrant EZH2 in hepatoblastoma

Lara Berklite, Priyanka Rao, Emily Schepers, Andrew Badachhape, Somak Roy, Greg Tiao, Bruce J. Aronow, Sarangarajan Ranganathan, James I. Geller, Erica A. K. Depasquale, Sarah E. Woodfield, Nikolai A. Timchenko, Brian T Hickner, Alexander J. Bondoc, Kathryn Glaser, Roma H. Patel, Sanjeev A. Vasudevan
article en

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.

Scientific ReportsVol. 16(1)
Cincinnati Children's Hospital Medical Center (US), Baylor College of Medicine (US), University of California San Diego (US), Rady Children's Hospital-San Diego (US), Center for Cancer and Blood Disorders (US), Stanford Medicine (US), Texas Children's Hospital (US), Children's Cancer Center (US), University of Cincinnati (US), University of Cincinnati Medical Center (US), The University of Osaka (JP)
Good health and well-being
Openalex Percentile: Top 65%
Epigenetics and DNA Methylation
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