Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2 (PRC2), catalyzes the methylation of lysine 27 of histone H3 (H3K27) up to its trimethylated form (H3K27me), inducing by this way block of transcription and gene silencing. High levels of H3K27me3 have been found in both hematological malignancies and solid cancers, due to EZH2 overexpression and/or EZH2 mutation[2]. EI1 is highly selective against Ezh2 over its close homolog Ezh1. The IC50 value of EI1 increased linearly with increasing concentration of S-Adenosyl methionine (SAM). Although SAM is the common cofactor for all HMTs, EI1 displayed ∼90-fold selectivity for Ezh2 over Ezh1, and >10,000-fold selectivity over other HMTs. EI1 dramatically inhibited the H3K27me3 and H3K27me2 levels in these cells in a dose-dependent manner. It inhibits cellular H3K27 methylation and activates Ezh2 target gene expression. EI1 treatment mimics Ezh2 knockout in the MEFs to inhibit H3K27me3 and cell proliferation. The proliferation of Ezh2 mutant DLBCL cells, including WSU-DLCL2, SU-DHL6, Karpas422, DB, and SU-DHL4, was strongly inhibited by EI1 in a dose-dependent manner. Cyclin A and B1 protein levels were diminished after 6 d of EI1 treatment. A mild increase of sub-G1 population was observed in EI1-treated SU-DHL6 and Karpas422, suggesting an increase of apoptosis[3]. In cancer cells, EI1 inhibited the proliferation of lymphomas expressing gain-of-function mutated EZH2 with a decrease of H3K27me3 levels and activation of transcription of gene targets, while the growth of wild-type EZH2 cells was only weakly inhibited.
作用机制
EI1 inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine[2].
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