Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer Sci. 2018 Jun;109(6):1853-1864. doi: 10.1111/cas.13599. Epub 2018 May 15.
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.
增强子结合锌指蛋白 2（EZH2）在广泛的肿瘤中过度表达，通过多种不同的方式促进卵巢癌的恶性程度。我们旨在说明 EZH2 在卵巢癌顺铂耐药中的作用，并确定该作用的可能潜在机制，这些机制可能为癌症治疗中靶向 EZH2 提供依据。在这里，我们提供的数据表明，EZH2 的过表达与顺铂耐药和细胞内铂类药物蓄积有关。对 84 名卵巢癌患者的 EZH2 水平进行测量，表明 EZH2 水平高的患者对顺铂的反应往往较差。接受重复顺铂暴露的细胞中 EZH2 水平逐渐升高。EZH2 的下调不仅使细胞对顺铂的反应更加敏感，并增加了细胞内铂蓄积，当细胞同时接受顺铂和 BODIPY-Pt（一种荧光顺铂复合物）时，还能保护铜转运蛋白 1（一种与顺铂耐药密切相关的高亲和力铜转运蛋白）免受顺铂诱导的蛋白酶体降解。总的来说，这些发现确定了一个新的机制，扩大了 EZH2 在卵巢癌顺铂耐药中的未被认识的作用。
