Pediatric blood & cancer · 2023
EZH2 is a key component of hepatoblastoma tumor cell growth.
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Glaser Kathryn, Schepers Emily J, Zwolshen Harrison M, Lake Charissa M, Timchenko Nikolai A, Karns Rebekah A, Cairo Stefano, Geller James I, Tiao Gregory M, Bondoc Alexander J
Аннотация
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.
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.