EZH2 is a key component of hepatoblastoma tumor cell growth.

Autor: Glaser K; Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Schepers EJ; Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Zwolshen HM; Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Lake CM; Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Timchenko NA; Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Karns RA; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Cairo S; Champions Oncology, US Research Headquarters, Rockville, Maryland, USA., Geller JI; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Tiao GM; Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Bondoc AJ; Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Jazyk: angličtina
Zdroj: Pediatric blood & cancer [Pediatr Blood Cancer] 2024 Feb; Vol. 71 (2), pp. e30774. Date of Electronic Publication: 2023 Nov 21.
DOI: 10.1002/pbc.30774
Abstrakt: 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.
(© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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