Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

Enhancer of zeste homolog 2 (EZH2), which is overexpressed in a wide range of tumors, contributes to ovarian cancer malignancy in several different ways. We aimed to illustrate the role of EZH2 in ovarian cancer cisplatin resistance and to identify possible underlying mechanisms of this role that may provide a rationale for targeting EZH2 in cancer treatment. Here, we present data indicating that EZH2 overexpression is associated with cisplatin resistance and intracellular platinum drug accumulation. Measurements of EZH2 in 84 ovarian cancer patients suggested that patients with high EZH2 levels tend to have poor responses to cisplatin. The EZH2 level progressively increased in cells receiving repeated cisplatin exposure. Downregulation of EZH2 not only sensitized cellular reactions to cisplatin and increased cellular platinum accumulation when cells were exposed to both cisplatin and BODIPY-Pt (a fluorescent cisplatin complex) but also protected copper transporter 1, a high-affinity copper transporter closely related to cisplatin resistance, from cisplatin-induced proteasomal degradation. Overall, these findings identify a new mechanism that expands the unrecognized role of EZH2 in ovarian cancer cisplatin resistance.