The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer.
The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer.
复制标题
组蛋白去甲基化酶KDM4B调节卵巢癌的腹膜种植。
DOI：
10.1038/onc.2016.412
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发表时间：
2017-05-04
期刊：
影响因子：
8
通讯作者：
Krieg AJ
中科院分区：
文献类型：
--
作者：
Wilson C;Qiu L;Hong Y;Karnik T;Tadros G;Mau B;Ma T;Mu Y;New J;Louie RJ;Gunewardena S;Godwin AK;Tawfik OW;Chien J;Roby KF;Krieg AJ
上皮性卵巢癌（EOC）预后差，复发快，因为广泛传播的腹膜转移在诊断。多种途径导致卵巢癌的侵袭性，包括缺氧信号机制。在这项研究中，我们已经确定，缺氧诱导的组蛋白去甲基化酶KDM 4 B表达在约60%的EOC肿瘤检测，包括原发性和匹配的转移性肿瘤。KDM 4 B在肿瘤中的表达与肿瘤缺氧标志物CA-IX的表达正相关，并且在暴露于缺氧的EOC细胞系中被强烈诱导。KDM 4 B调节转移基因和途径的表达，并且KDM 4 B的缺失增加靶基因如L0 XL 2、LCN 2和PDGFB的启动子处的H3 K9三甲基化。抑制KDM 4 B抑制卵巢癌细胞体外侵袭、迁移和球体形成。KDM 4 B还调节体内腹膜肿瘤的接种和生长，其中其表达对应于缺氧区域。这是第一次证明Jumonji结构域组蛋白去甲基化酶调节癌细胞腹膜播散所需的细胞过程，这是影响EOC预后的主要因素之一。KDM 4 B调节的途径可能为开发组合疗法提供新的机会，以改善EOC患者的现有疗法。
Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60% of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes and pathways, and loss of KDM4B increases H3K9 trimethylation at the promoters of target genes like LOXL2, LCN2 and PDGFB. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B also regulates seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. This is the first demonstration that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC. The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.