State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Department of Gynecological Oncology, Hubei Cancer Hospital, Wuhan 430071, China.
EBioMedicine. 2021 Sep;71:103558. doi: 10.1016/j.ebiom.2021.103558. Epub 2021 Sep 11.
Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC.
ZNF711 expression in 150 EOC specimens was examined using immunohistochemistry. ZNF711 expression and the survival of EOC patients were assessed with a Kaplan-Meier analysis. The effects of ZNF711 expression on CDDP resistance were studied by IC50, Annexin V, and colony formation in vitro, and in an in vivo intra-peritoneal tumor model. The molecular mechanism was determined using a luciferase reporter assay, ChIP assay, CAPTURE approach, and co-IP assay.
ZNF711 down-regulation exerts a great impact on CDDP resistance for EOC patients by suppressing SLC31A1 and inhibiting CDDP influx. ZNF711 down-regulation promoted, while ZNF711 overexpression drastically inhibited CDDP resistance, both in vivo and in vitro. Mechanistically, the histone demethylase JHDM2A was recruited to the SLC31A1 promoter by ZNF711 and decreased the H3K9me2 level, resulting in the activation of SLC31A1 transcription and enhancement of CDDP uptake. Importantly, co-treatment with the histone methylation inhibitor, BIX-01294, increased the therapeutic efficacy of CDDP treatment in ZNF711-suppressed EOC cells.
These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment.
This work was supported by the Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities; and China Postdoctoral Science Foundation.
上皮性卵巢癌（EOC）患者在治疗过程中对铂类化疗的耐药性是治疗失败的主要原因。我们的研究旨在阐明 ZNF711 下调促进 EOC 中顺铂耐药的分子机制。
采用免疫组织化学法检测 150 例 EOC 标本中 ZNF711 的表达。采用 Kaplan-Meier 分析评估 ZNF711 表达与 EOC 患者生存的关系。通过体外 IC50、Annexin V 和集落形成实验以及体内腹腔肿瘤模型研究 ZNF711 表达对 CDDP 耐药性的影响。采用荧光素酶报告基因检测、ChIP 检测、CAPTURE 法和 co-IP 检测确定分子机制。
ZNF711 下调通过抑制 SLC31A1 并抑制 CDDP 内流，对 EOC 患者的 CDDP 耐药性产生重大影响。ZNF711 下调促进了体内和体外的 CDDP 耐药性，而 ZNF711 过表达则极大地抑制了 CDDP 耐药性。机制上，组蛋白去甲基化酶 JHDM2A 被 ZNF711 募集到 SLC31A1 启动子上，降低了 H3K9me2 水平，导致 SLC31A1 转录激活和 CDDP 摄取增强。重要的是，与组蛋白甲基化抑制剂 BIX-01294 联合治疗可增加 ZNF711 抑制的 EOC 细胞中 CDDP 治疗的疗效。
这些发现验证了 ZNF711 在 CDDP 耐药性中的临床重要性，并为 EOC 治疗提供了新的治疗方案。
本工作得到了中国自然科学基金；广州市科技计划项目；广东省自然科学基金；中央高校基本科研业务费专项资金；中国博士后科学基金的资助。
