Noonan E J, Place R F, Pookot D, Basak S, Whitson J M, Hirata H, Giardina C, Dahiya R
Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA.
Oncogene. 2009 Apr 9;28(14):1714-24. doi: 10.1038/onc.2009.19. Epub 2009 Mar 2.
Histone deacetylases (HDACs) are frequently overexpressed 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.
组蛋白去乙酰化酶（HDACs）在多种癌症类型中经常过度表达，在这些癌症中，它们会改变细胞的表观遗传程序以促进细胞增殖和存活。然而，HDACs在人类癌症中过度表达的机制仍有些神秘。在本研究中，我们调查了miR-449a在前列腺癌细胞中的表达及其功能意义。通过实时PCR，我们发现相对于患者匹配的对照组织，miR-449a在前列腺癌组织中表达下调。将miR-449a导入PC-3前列腺癌细胞会导致细胞周期停滞、凋亡以及类似衰老的表型。对3'-UTR区域的计算机分析确定了一些参与细胞周期调控的基因作为miR-449a的假定靶标。使用荧光素酶3'-UTR报告系统，我们确定HDAC-1（组蛋白去乙酰化酶1）是miR-449a的直接靶标，HDAC-1在多种癌症类型中经常过度表达。此外，我们的数据表明，miR-449a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在正常组织与癌组织中调节HDAC表达的功能提供了新的见解。
