High levels of intracellular polyamines promote histone acetyltransferase activity resulting in chromatin hyperacetylation
High levels of intracellular polyamines promote histone acetyltransferase activity resulting in chromatin hyperacetylation
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DOI：
10.1002/(sici)1097-4644(20000601)77:3
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发表时间：
2000-01-01
影响因子：
4
通讯作者：
Gilmour, SK
中科院分区：
文献类型：
--
作者：
Hobbs, CA;Gilmour, SK
多胺刺激多种基因的表达，包括许多与细胞增殖有关的基因。事实上，鸟氨酸脱羧酶（ODC）的异常表达，多胺生物合成中的限速酶，在肿瘤发生中起着因果作用。基因活性受核小体组蛋白乙酰化的动态变化影响。虽然多胺在无细胞系统中影响组蛋白乙酰转移酶和去乙酰化酶的活性，但它们在活细胞中调节这些酶的能力尚未确定。为了研究细胞内ODC和多胺水平升高对基因转录和组蛋白乙酰化的影响，我们用含有ODC cDNA的逆转录病毒感染细胞。ODC过表达增强了组蛋白去乙酰化酶抑制剂对报告基因表达的刺激作用，超出了ODC或抑制剂单独治疗的促进作用。事实上，细胞内ODC水平的升高促进了几种表皮细胞和成纤维细胞类型中组蛋白的超乙酰化。当细胞用α -二氟甲基鸟氨酸（一种ODC活性的特异性抑制剂）处理时，ODC介导的乙酰化组蛋白的增加被消除，这意味着多胺的独特作用。具体来说，多胺被发现可以直接或间接地增强组蛋白乙酰转移酶的作用。我们的研究记录了细胞内多胺水平升高对增殖细胞中组蛋白乙酰化的影响，提示了多胺生物合成改变导致基因异常表达，促进肿瘤生长的机制。此外，这些研究可能对设计用于调节修饰组蛋白乙酰化状态的酶的药物的开发具有启示意义。j .细胞。生物化学学报。37(3):345- 336,2000。(C) 2000 Wiley-Liss, inc。
Polyamines stimulate expression of a variety of genes, including many implicated in cell proliferation. indeed, aberrant expression of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis, plays a causal role in tumorigenesis. Gene activity is influenced by dynamic changes in acetylation of nucleosomal histones. Although polyamines influence the histone acetyltransferase and deacetylase activities in cell-free systems, their ability to modulate these enzymes in live cells has never been established. To examine the effects of elevated intracellular levels of ODC and polyamines on gene transcription and histone acetylation, cells were infected with a retrovirus containing a cDNA for ODC. ODC overexpression potentiated the stimulatory effects of histone deacetylase inhibitors on reporter gene expression beyond that promoted by ODC or inhibitor treatment alone. Indeed, elevated intracellular levels of ODC promoted hyperacetylation of histones in several epidermal and fibroblast cell types. The ODC-mediated increase in acetylated histones was abrogated when cells were treated with alpha-difluoromethylornithine, a specific inhibitor of ODC activity, implying a distinct role for polyamines. Specifically, polyamines were found to enhance the action of histone acetyltransferases either directly or indirectly. Our studies document effects of elevated intracellular polyamine levels on histone acetylation in proliferating cells, suggesting a mechanism by which altered polyamine biosynthesis contributes to aberrant expression of genes, facilitating tumor growth. In addition, these studies may have implications for the development of drugs designed to regulate enzymes that modify the acetylation status of histones. J. Cell. Biochem. 77:345-360, 2000. (C) 2000 Wiley-Liss, inc.