EZH2 inhibitor Tazemetostat synergizes with JQ-1 in esophageal cancer by inhibiting c-Myc signaling pathway.

Abstract

EZH2, a highly conserved histone methyltransferase, plays an essential role in tumorigenesis and development. The inhibitor of EZH2 tazemetostat has been approved to treat metastatic or locally advanced epithelioid sarcoma and recurrent or refractory follicular lymphoma. However, the effect of tazemetostat alone or in combination with other drugs in esophageal cancer has not been reported. In this study, we found that EZH2 was highly expressed in esophageal cancer at both mRNA and protein levels through transcriptomic and proteomic analyses. Furthermore, the results of CCK8, colony formation, cell cycle and cell apoptosis assays revealed that tazemetostat exerted an antitumour effect on esophageal cancer cells. Mechanistically, RNA-sequencing analysis of the tazemetostat-treated cells and vehicle-treated ones suggested that tazemetostat mainly inhibited the c-Myc signaling pathway and its targets, which was validated by western blotting. JQ-1, an inhibitor of bromodomain 4, was proven to attenuate c-Myc signaling in tumors. Thus, a therapeutic strategy based on tazemetostat in combination with JQ-1 is promising. The results demonstrated that tazemetostat and JQ-1 had a synergistic effect in vitro and in vivo for esophageal cancer.