EZH2: Role in breast cancer and potential therapeutic applications

Abstract

Human diseases, most notably cancer, are frequently associated with epigenetic dysregulation. Epigenetic modifications control gene function beyond the underlying sequence and are heritable but reversible alterations in histones or DNA. EZH2 is a critical epigenetic factor, member of the Polycomb group with H3K27me3 methyltransferase activity. Previous studies have demonstrated that EZH2 can function as an oncogene in a variety of breast cancer subtypes and that higher EZH2 expression levels are associated with more aggressive disease outcomes. By epigenetic interference with the WNT signaling pathway, EZH2 stimulates breast tumor development. Nowadays many EZH2 inhibitors are designed to specifically target either its catalytic or its non-catalytic function. This bibliographical review focuses on the significance of EZH2 in luminal B and Triple-Negative Breast cancer, as well as on two EZH2 inhibitors, namely Tazemetostat (EPZ6438) and GSK126, which target its catalytic methyltransferase activity. Targeting the catalytic domain results in a significant delay in tumor formation and inhibition of the metastatic capacity of the tumor, in models mimicking luminal B breast cancer and TNBC mouse models. EZH2 was also found to promote breast cancer bone metastases in vivo. This review also focuses on efforts to target the non-catalytic functions of EZH2, such as ZRANB1 deubiquitinase, targeting of which reduces cell migration and proliferation. Overall, EZH2 seems to be a very promising target to use in therapies against breast cancer, but further work is necessary to lead to clinical trial applications.