Kuang Yan, Lu Fangfang, Guo Jianfeng, Xu Hong, Wang Qi, Xu Chaohuan, Zeng Longjia, Yi Suyi
Department of Obstetrics and Gynecology, First Affiliated Hospital of Guangxi Medical University, Nanning.
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Onco Targets Ther. 2017 Jun 26;10:3131-3144. doi: 10.2147/OTT.S134784. eCollection 2017.
Aberrant histone methylation contributes to the progression and development of many tumors. Histone methylation is a dynamic process regulated by both histone demethylase and histone methyltransferase, which ultimately alters the levels of gene transcription. However, the relationship between histone demethylase and histone methyltransferase, as well as their regulatory mechanisms in ovarian cancer development, is still unclear. Lysine-specific demethylase 2B (KDM2B) is a key demethylase of H3K36me3 and H3K4me3 that regulates gene expression and plays a role in tumorigenesis via epigenetic mechanisms. To determine the expression pattern of KDM2B in ovarian neoplasms, we analyzed the mRNA and protein levels of KDM2B and the histone methyltransferase enhancer of zester homolog 2 (EZH2) in normal, benign, borderline, and malignant ovarian tissue samples. We found that KDM2B expression was gradually increased in ovarian tumors, with the highest expression found in the malignant ovarian tissues, and the differences in KDM2B expression among the different International Federation of Gynecology and Obstetrics stages and pathological grades/types were statistically significant. Moreover, KDM2B expression was positively correlated with EZH2 expression in ovarian tissues. To determine the role of KDM2B in tumorigenesis in vitro and in vivo, we silenced KDM2B expression in ovarian cancer cells using the KDM2B short hairpin RNA expression lentivirus and established a nude mouse xenograft model. Downregulation of endogenous KDM2B decreased the expression of EZH2 and reduced the proliferation and migration of ovarian cancer cells. Loss of KDM2B suppressed ovarian tumor formation in vivo. Our results suggest that KDM2B plays an important role in the tumorigenesis of ovarian cancer, with a possible mechanism of increasing the expression of the oncogene ; this indicates that certain histone methyltransferase may be positively regulated by certain histone demethylase in the epigenetic regulation of ovarian tumors. KDM2B may be a novel therapeutic target for the clinical treatment of ovarian cancer.
异常的组蛋白甲基化促进了许多肿瘤的进展和发展。组蛋白甲基化是一个由组蛋白去甲基化酶和组蛋白甲基转移酶共同调节的动态过程，最终改变基因转录水平。然而，组蛋白去甲基化酶与组蛋白甲基转移酶之间的关系及其在卵巢癌发生发展中的调控机制仍不清楚。赖氨酸特异性去甲基化酶2B（KDM2B）是H3K36me3和H3K4me3的关键去甲基化酶，它通过表观遗传机制调节基因表达并在肿瘤发生中发挥作用。为了确定KDM2B在卵巢肿瘤中的表达模式，我们分析了正常、良性、交界性和恶性卵巢组织样本中KDM2B以及组蛋白甲基转移酶zeste同源物2增强子（EZH2）的mRNA和蛋白水平。我们发现KDM2B在卵巢肿瘤中的表达逐渐增加，在恶性卵巢组织中表达最高，且不同国际妇产科联盟分期和病理分级/类型之间KDM2B表达的差异具有统计学意义。此外，卵巢组织中KDM2B的表达与EZH2的表达呈正相关。为了确定KDM2B在体外和体内肿瘤发生中的作用，我们使用KDM2B短发夹RNA表达慢病毒沉默卵巢癌细胞中KDM2B的表达，并建立了裸鼠异种移植模型。内源性KDM2B的下调降低了EZH2的表达，减少了卵巢癌细胞的增殖和迁移。KDM2B的缺失在体内抑制了卵巢肿瘤的形成。我们的结果表明，KDM2B在卵巢癌的肿瘤发生中起重要作用，其可能的机制是增加癌基因的表达；这表明在卵巢肿瘤的表观遗传调控中，某些组蛋白甲基转移酶可能受到某些组蛋白去甲基化酶的正调控。KDM2B可能是卵巢癌临床治疗的一个新的治疗靶点。
