Rapid alteration of microRNA levels by histone deacetylase inhibition
Rapid alteration of microRNA levels by histone deacetylase inhibition
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DOI：
10.1158/0008-5472.can-05-3632
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Benz, CC
中科院分区：
文献类型：
--
作者：
Scott, GK;Mattie, ND;Benz, CC
深入了解组蛋白脱乙酰酶(HDAC)小分子抑制剂诱导细胞分化和凋亡的分子机制，无疑将有助于其作为抗癌药物的临床发展。作为基因转录水平的调节因子，HDAC抑制剂(HDACi)通常只影响5%-10%的活跃转录基因，上调和下调的mRNA转录本数量大致相同。利用microRNA(MiRNA)阵列分析，我们报告了乳腺癌细胞株SKBr3中miRNA水平的快速变化，以响应强大的异羟肟酸HDACi LAQ824。在暴露于促凋亡剂量的LAQ824的5小时内，SKBr3细胞中40%的>；60种不同miRNA的表达发生了显著变化，其中22种miRNA表达下调，5种miRNA表达上调。为了探讨HDACi诱导的miR-27a和miR-27b表达上调和miRNA下调之间的潜在功能联系，我们对LAQ824在SKBr3细胞中大量表达和下调的miR-27a和miR-27b进行了反义实验。将先前由LAQ824在SKBr3中快速上调的一组基因与潜在的3‘非翻译区miRNA结合元件数据库相关联，发现两个含有miR-27锚定元件的基因在miR-27反义转染后转录上调，ZBTB10/RINZF是Sp1抑制因子，RYBP/DEDAF是凋亡促进因子。这些发现强调了HDACi转录后mRNA调控的重要性，以及它们对启动子驱动的基因表达的既定作用。
Improved understanding of the molecular mechanisms by which small-molecule inhibitors of histone deacetylases (HDAC) induce programs, such as cellular differentiation and apoptosis, would undoubtedly assist their clinical development as anticancer agents. As modulators of gene transcript levels, HDAC inhibitors (HDACi) typically affect only 5% to 10% of actively transcribed genes with approximately as many mRNA transcripts being up-regulated as down-regulated. Using microRNA (miRNA) array analysis, we report rapid alteration of miRNA levels in response to the potent hydroxamic acid HDACi LAQ824 in the breast cancer cell line SKBr3. Within 5 hours of exposure to a proapoptotic dose of LAQ824, significant changes were measured in 40% of the > 60 different miRNA species expressed in SKBr3 cells with 22 miRNA species down-regulated and 5 miRNAs upregulated. To explore a potential functional link between HDACi induced mRNA up-regulation and miRNA down-regulation, antisense experiments were done against miR-27a and miR-27b, both abundantly expressed and down-regulated in SKBr3 cells by LAQ824. Correlating a set of genes previously determined by cDNA array analysis to be rapidly up-regulated by LAQ824 in SKBr3 with a database of potential 3' untranslated region miRNA binding elements, two genes containing putative miR-27 anchor elements were identified as transcriptionally up-regulated following miR-27 antisense transfection, ZBTB10/RINZF, a Sp1 repressor, and RYBP/DEDAF, an apoptotic facilitator. These findings emphasize the importance of post-transcriptional mRNA regulation by HDACi in addition to their established effects on promoter-driven gene expression.