EZH2 is a key prognostic marker and therapeutic target in aggressive and proliferative hepatoblastoma

EZH2 is a histone methyltransferase and a key component of polycomb repressive complex 2 (PRC2). It plays a critical role in genome remodeling, gene regulation and acts through PRC2-dependent and independent mechanisms, which comprise methylation of histone and non-histone substrates, and transcriptional activation through different transcriptional complexes. EZH2 is involved in many cancers, but its role in hepatoblastoma is poorly understood. Potential correlation between EZH2 mRNA expression and clinical parameters was analyzed by computational and histological approaches using seven published transcriptomic datasets and tissue samples from patients with hepatoblastoma. EZH2 molecular function was deciphered using molecular approaches, gain- and loss-of-function genetic tools, proteomics, immunohistochemistry, pharmacological drugs, 2D cell- and spheroid-based assays, and four different animal models. Our data show that EZH2 mRNA expression correlated with poor prognostic markers such as tumor proliferation, and patients’ death and shorter survival. EZH2 protein potentiated hepatoblastoma cell proliferation, migration, survival and cisplatin resistance through its histone methyltransferase activity by repressing DUSP5, and transcriptionally inducing DUSP9 and HMGCR. In vivo EZH2 sustained tumor cell proliferation, and tumor development and angiogenesis. The EZH2 inhibitor GSK126 synergized with HMG-CoA reductase inhibitor statins to eradicate hepatoblastoma cells in vitro and block tumor development in mice. This combination was also very effective on various hepatoblastoma and non-hepatoblastoma tumor cell lines. Collectively, our data showed that the protein EZH2 promotes hepatoblastoma development, partly through its histone methyltransferase activity, by differentially modulating the expression of DUSP5, DUSP9 and HMGCR genes and by supporting the MAPK/ERK pathway in hepatoblastoma cells already displaying high Wnt signal activity. EZH2 inhibitors triggered lipid synthesis in hepatoblastoma cells and synergized with cholesterol-lowering statins to block hepatoblastoma development in vitro and in vivo. Therefore, we demonstrate the key role of EZH2 in proliferative hepatoblastoma and the therapeutic benefit of combining EZH2 inhibitor and statin to treat patients with cancer.