Histone demethylase KDM2B upregulates histone methyltransferase EZH2 expression and contributes to the progression of ovarian cancer in vitro and in vivo.
Histone demethylase KDM2B upregulates histone methyltransferase EZH2 expression and contributes to the progression of ovarian cancer in vitro and in vivo.
复制标题
组蛋白去甲基化酶 KDM2B 上调组蛋白甲基转移酶 EZH2 表达并促进卵巢癌的体外和体内进展
DOI：
10.2147/ott.s134784
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发表时间：
2017
影响因子：
4
通讯作者：
Yi S
中科院分区：
文献类型：
--
作者：
Kuang Y;Lu F;Guo J;Xu H;Wang Q;Xu C;Zeng L;Yi S
异常的组蛋白甲基化有助于许多肿瘤的进展和发展。组蛋白甲基化是一个受组蛋白去甲基化酶和组蛋白甲基转移酶共同调控的动态过程，最终改变基因转录水平。然而，组蛋白去甲基化酶和组蛋白甲基转移酶之间的关系，以及它们在卵巢癌发生中的调节机制，仍然不清楚。赖氨酸特异性去甲基化酶2B（KDM 2B）是H3 K36 me 3和H3 K4 me 3的关键去甲基化酶，其调节基因表达并通过表观遗传机制在肿瘤发生中起作用。为了确定KDM 2B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KDM 2B和组蛋白甲基转移酶增强子zester同源物2（EZH 2）的mRNA和蛋白水平。我们发现KDM 2B在卵巢肿瘤中的表达逐渐增加，在卵巢恶性肿瘤组织中表达最高，不同国际妇产科联合会分期和病理分级/分型间KDM 2B的表达差异有统计学意义。卵巢组织中KDM 2B表达与EZH 2表达呈正相关。为了确定KDM 2B在体外和体内肿瘤发生中的作用，我们使用KDM 2B短发夹RNA表达慢病毒沉默卵巢癌细胞中的KDM 2B表达，并建立裸鼠异种移植模型。内源性KDM 2B的下调可降低EZH 2的表达，并降低卵巢癌细胞的增殖和迁移。KDM 2B的缺失抑制体内卵巢肿瘤形成。我们的研究结果表明，KDM 2B在卵巢癌的发生中起着重要的作用，其可能的机制是增加癌基因EZH 2的表达;这表明某些组蛋白甲基转移酶可能正调控某些组蛋白去甲基化酶在卵巢肿瘤的表观遗传调控。KDM 2B可能成为卵巢癌临床治疗的新靶点。
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 EZH2; 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.