miR-449a targets HDAC-1 and induces growth arrest in prostate cancer
miR-449a targets HDAC-1 and induces growth arrest in prostate cancer
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DOI：
10.1038/onc.2009.19
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发表时间：
2009-04-09
期刊：
影响因子：
8
通讯作者：
Dahiya, R.
中科院分区：
文献类型：
--
作者：
Noonan, E. J.;Place, R. F.;Dahiya, R.
组蛋白去乙酰化酶（HDAC）经常在广泛的癌症类型中过表达，其中它们改变细胞表观遗传编程以促进细胞增殖和存活。然而，HDAC在人类癌症中过度表达的机制仍然是一个谜。在本研究中，我们研究了miR-449 a在前列腺癌细胞中的表达及其功能意义。使用实时PCR，我们发现miR-449 a在前列腺癌组织中相对于患者匹配的对照组织下调。将miR-449 a导入PC-3前列腺癌细胞导致细胞周期停滞、凋亡和衰老样表型。对3 '-UTR区域的计算机分析鉴定了参与细胞周期调控的许多基因作为miR-449 a的推定靶点。使用荧光素酶3 '-UTR报告系统，我们确定了HDAC-1（组蛋白脱乙酰基酶1），一种在许多类型的癌症中经常过表达的基因，是miR-449 a的直接靶点。此外，我们的数据表明，miR-449 a部分通过抑制前列腺癌细胞中HDAC-1的表达来调节细胞生长和活力。我们的研究结果为miRNA在调节正常组织和癌组织中HDAC表达的功能提供了新的见解。
Histone deacetylases (HDACs) are frequently over-expressed in broad range of cancer types, where they alter cellular epigenetic programming to promote cell proliferation and survival. However, the mechanism by which HDACs become overexpressed in human cancers remains somewhat of a mystery. In this study, we investigated the expression and functional significance of miR-449a in prostate cancer cells. Using real-time PCR, we found that miR-449a is downregulated in prostate cancer tissues relative to patient-matched control tissue. Introduction of miR-449a into PC-3 prostate cancer cells resulted in cell-cycle arrest, apoptosis and a senescent-like phenotype. In silico analysis of 3'-UTR regions identified a number of genes involved in cell-cycle regulation as putative targets of miR-449a. Using a luciferase 3'-UTR reporter system, we established that HDAC-1 (histone deacetylase 1), a gene that is frequently overexpressed in many types of cancer, is a direct target of miR-449a. Further, our data indicate that miR-449a regulates cell growth and viability in part by repressing the expression of HDAC-1 in prostate cancer cells. Our findings provide new insight into the function of miRNA in regulating HDAC expression in normal versus cancerous tissue.