Comparison of the antineoplastic action of 3-deazaneplanocin-A and inhibitors that target the catalytic site of EZH2 histone methyltransferase

EZH2 is the histone methyltransferase (HMT) that catalyzes the trimethylation of histone H3 lysine 27 (H3K27me3), a histone marker that silences gene expression. Overexpression of EZH2 enhances the growth of malignant cells due to silencing of tumor suppressor genes (TSGs). 3-deazaneplanocin-A (DZNep) blocks the metabolism of methionine resulting in global inhibition of HMTs, including EZH2. This action of DZNep leads to inhibition of growth of malignant cells and reactivation of TSGs. On the other hand, specific inhibitors that target the catalytic site of EZH2: GSK-126, GSK-343, CPI-1205, and tazemetostat (EPZ-6438) were also investigated and exhibited interesting antineoplastic activity. These studies indicated that their anticancer action required a longer duration of treatment than DZNep to exhibit significant antineoplastic activity. This observation suggests that DZNep is a more potent antineoplastic agent than the specific EZH2 inhibitors. Such a difference in anticancer potency may be explained in part by the limited penetration into cells of the specific EZH2 inhibitors due to their large complex molecular structure as compared to the smaller molecular size of DZNep. An additional explanation is that DZNep has several targets in the cell which contribute to its anticancer action: deregulation of methionine metabolism, proteosomal degradation of EZH2, and activation of miRNAs with TSG function. In this study, we compared the in vitro antineoplastic action of DZNep and the specific EZH2 inhibitors using growth inhibition and colony assays on leukemic cells. These assays confirm that DZNep is a more potent anticancer agent than the specific EZH2 inhibitors. DZNep merits clinical investigation in patients with cancer.