EZH2 is a key component of hepatoblastoma tumor cell growth

Pediatr Blood Cancer. 2024 Feb;71(2):e30774. doi: 10.1002/pbc.30774. Epub 2023 Nov 21.


Background: Enhancer of zeste homolog 2 (EZH2) catalyzes the trimethylation of histone H3 at lysine 27 via the polycomb recessive complex 2 (PRC2) and plays a time-specific role in normal fetal liver development. EZH2 is overexpressed in hepatoblastoma (HB), an embryonal tumor. EZH2 can also promote tumorigenesis via a noncanonical, PRC2-independent mechanism via proto-oncogenic, direct protein interaction, including β-catenin. We hypothesize that the pathological activation of EZH2 contributes to HB propagation in a PRC2-independent manner.

Methods and results: We demonstrate that EZH2 promotes proliferation in HB tumor-derived cell lines through interaction with β-catenin. Although aberrant EZH2 expression occurs, we determine that both canonical and noncanonical EZH2 signaling occurs based on specific gene-expression patterns and interaction with SUZ12, a PRC2 component, and β-catenin. Silencing and inhibition of EZH2 reduce primary HB cell proliferation.

Conclusions: EZH2 overexpression promotes HB cell proliferation, with both canonical and noncanonical function detected. However, because EZH2 directly interacts with β-catenin in human tumors and EZH2 overexpression is not equal to SUZ12, it seems that a noncanonical mechanism is contributing to HB pathogenesis. Further mechanistic studies are necessary to elucidate potential pathogenic downstream mechanisms and translational potential of EZH2 inhibitors for the treatment of HB.

Keywords: HB tumor-derived cell line; PRC2; organoid; β-catenin.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Female
  • Hepatoblastoma* / genetics
  • Humans
  • Liver Neoplasms* / pathology
  • Polycomb Repressive Complex 2 / metabolism
  • Pregnancy
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Enhancer of Zeste Homolog 2 Protein
  • beta Catenin
  • Polycomb Repressive Complex 2
  • EZH2 protein, human