Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer
Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer
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DOI：
10.1074/jbc.m501379200
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发表时间：
2005-06-10
影响因子：
4.8
通讯作者：
Hsieh, JT
中科院分区：
文献类型：
--
作者：
Chen, H;Tu, SW;Hsieh, JT
人DAB2IP（human DAB2IP，hDAB2IP）是一种新型的GTP酶激活蛋白，可调节Ras介导的信号转导和肿瘤坏死因子介导的细胞凋亡，是前列腺癌的生长抑制剂。PCa中hDAB2IP表达的缺失是由于其启动子区域的表观遗传调控（即DNA甲基化和组蛋白修饰）改变。组蛋白甲基转移酶polycomb Ezh2的升高与PCa进展相关。在这项研究中，我们已经证明，Ezh2在正常前列腺上皮细胞中的表达增加可以抑制hDAB2IP基因的表达。相反，通过特异性小干扰RNA敲低PCa中内源性Ezh2水平可以增加hDAB2IP表达。Ezh2复合物（包括Eed和Suz12）与hDAB2IP基因启动子的结合在PCa细胞中也被检测到，而在正常前列腺上皮细胞中未检测到。通过cDNA转染在正常前列腺上皮细胞中增加Ezh2表达促进Ezh2复合物的其他组分募集到hDAB2IP启动子区域，伴随着甲基组蛋白H3（H3）和组蛋白脱乙酰酶（HDAC 1）水平的增加。结果表明，Ezh2小分子干扰RNA转染PCa细胞后，Ezh2复合物的解离与H3和HDAC1的表达水平降低有关。结果表明，hDAB2IP基因启动子区H3的Lys-27甲基化状态与正常前列腺上皮细胞和PCa细胞中hDAB2IP基因的甲基化水平一致，而H3的Lys-9甲基化状态与正常前列腺上皮细胞和PCa细胞中hDAB2IP基因的甲基化水平一致。结论：hDAB2IP基因是Ezh2在前列腺上皮中的靶基因，为hDAB2IP基因在前列腺癌中的下调提供了可能的机制。
Human DAB2IP ( hDAB2IP), a novel GTPase-activating protein modulating the Ras-mediated signaling and tumor necrosis factor-mediated apoptosis, is a potent growth inhibitor in human prostate cancer (PCa). Loss of hDAB2IP expression in PCa is due to altered epigenetic regulation (i.e. DNA methylation and histone modification) of its promoter region. The elevated polycomb Ezh2, a histone methyltransferase, has been associated with PCa progression. In this study, we have demonstrated that an increased Ezh2 expression in normal prostatic epithelial cells can suppress hDAB2IP gene expression. In contrast, knocking down the endogenous Ezh2 levels in PCa by a specific small interfering RNA can increase hDAB2IP expression. The association of Ezh2 complex (including Eed and Suz12) with hDAB2IP gene promoter is also detected in PCa cells but not in normal prostatic epithelial cells. Increased Ezh2 expression in normal prostatic epithelial cells by cDNA transfection facilitates the recruitment of other components of Ezh2 complex to the hDAB2IP promoter region accompanied with the increased levels of methyl histone H3 (H3) and histone deacetylase (HDAC1). Consistently, data from PCa cells transfected with Ezh2 small interfering RNA demonstrated that reduced Ezh2 levels resulted in the dissociation of Ezh2 complex accompanied with decreased levels of both methyl H3 and HDAC1 from hDAB2IP gene promoter. We further unveiled that the methylation status of Lys-27 but not Lys-9 of H3 in hDAB2IP promoter region is consistent with the hDAB2IP levels in both normal prostatic epithelial cells and PCa cells. Together, we conclude that hDAB2IP gene is a target gene of Ezh2 in prostatic epithelium, which provides an underlying mechanism of the down-regulation of hDAB2IP gene in PCa.