Epigenetic regulation of a novel tumor suppressor gene (hDAB2IP) in prostate cancer cell lines
Epigenetic regulation of a novel tumor suppressor gene (hDAB2IP) in prostate cancer cell lines
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DOI：
10.1074/jbc.m208230200
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发表时间：
2003-01-31
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;Toyooka, S;Hsieh, JT
hDAB 21 P（human DAB 2（also known as DOC-2）interactive protein）是一种新型的GTP酶激活蛋白，可调节Ras介导的信号通路。我们证明，hDAB 2 IP mRNA在前列腺癌（PCa）细胞中的下调是由转录水平调节。对hDAB 2 IP启动子的分析表明，它是一个典型的TATA-少启动子，含有许多富含GC的序列。在这项研究中，我们描绘了hDAB 2 IP启动子的表观遗传控制对PCa基因调控的潜在影响。乙酰组蛋白H3与hDAB 2 IP启动子相关，CpG岛在正常前列腺上皮细胞中几乎保持未甲基化，但在PCa细胞系中没有。我们的数据进一步表明，在PCa的hDAB 2 IP基因的表达调控中，组蛋白去乙酰化酶抑制剂（A）和DNA低甲基化剂（5 '-aza-2'-deoxycytidine）协同作用，而组蛋白乙酰化在此事件中发挥了更重要的作用。此外，还鉴定了负责这些处理的hDAB 2 IP基因的核心启动子序列。因此，我们的结论是，表观遗传调控在调节hDAB 2 IP在PCa中的表达中起着潜在的作用，这些结果也为PCa患者提供了一种新的治疗策略。
hDAB21P (human DAB2 (also known as DOC-2) interactive protein) is a novel GTPase-activating protein for modulating the Ras-mediated signal pathway. We demonstrate that the down-regulation of hDAB2IP mRNA in prostate cancer (PCa) cells is regulated by transcriptional levels. Analysis of the hDAB2IP promoter revealed that it is a typical TATA-less promoter containing many GC-rich sequences. In this study, we delineated the potential impact of the epigenetic control of the hDAB2IP promoter on its gene regulation in PCa. Acetylhistone H3 was associated with the hDAB2IP promoter, and CpG islands remained almost unmethylated in normal prostatic epithelia, but not in PCa cell lines. Our data further indicated that trichostatin A (histone deacetylase inhibitor) and 5'-aza-2'-deoxycytidine (DNA hypomethylation agent) acted cooperatively in modulating hDAB2IP gene expression in PCa, whereas histone acetylation played a more significant role in this event. Moreover, a core promoter sequence from the hDAB2IP gene responsible for these treatments was identified. We therefore conclude that epigenetic regulation plays a potential role in regulating hDAB2IP expression in PCa and that these results also provide a new therapeutic strategy for PCa patients.