Wei Gang, Hobbs Cheryl A, Defeo Karen, Hayes Candace S, Gilmour Susan K
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA.
Mol Carcinog. 2007 Aug;46(8):611-7. doi: 10.1002/mc.20350.
Overexpression of ornithine decarboxylase (ODC), resulting in increased polyamine metabolism, is a common feature of epithelial tumors. Polyamines play a complex role in promoting tumor development, affecting diverse cellular processes, including gene expression. One way polyamines may affect gene expression is to modulate the multiprotein complexes comprised of transcription factors and coregulatory factors that alter chromatin structure by acetylating/deacetylating nearby histones. We have capitalized on ODC-overexpressing cultured cells and K6/ODC and ODC/Ras transgenic mouse models, in which ODC overexpression is targeted to hair follicles, to evaluate the influence of polyamines on the acetylation of histones and other proteins. ODC overexpression was found to alter intrinsic histone acetyltransferase (HAT) and deacetylase activities and histone acetylation patterns. The high HAT activity exhibited by ODC transgenic mouse skin and tumors might be partly attributed to enhanced p300/creb-binding protein (CBP)-associated HAT activity and increased levels of Tat interactive protein, 60 kDa (Tip60) HAT protein isoforms. Altered association of Tip60 with E2F1 and a subset of newly identified Tip60-interacting transcription factors was detected in ODC mouse skin and tumors, implying novel polyamine modulation of Tip60-regulated gene expression. Polyamine effects on HAT enzymes also influence the acetylation status of nonhistone proteins. Overexpression of ODC in skin serves as a novel stimulus for acetylation of the tumor suppressor protein, p53--a target of both p300/CBP and Tip60--with concomitant increased binding to, and increased transcription of, a downstream target gene. The future challenge will be to elucidate the multiple mechanisms by which polyamines influence enzymes that regulate protein acetylation and gene transcription to promote cancer.
鸟氨酸脱羧酶（ODC）的过表达会导致多胺代谢增加，这是上皮肿瘤的一个常见特征。多胺在促进肿瘤发展中发挥着复杂的作用，影响包括基因表达在内的多种细胞过程。多胺影响基因表达的一种方式是调节由转录因子和共调节因子组成的多蛋白复合物，这些复合物通过使附近的组蛋白乙酰化/去乙酰化来改变染色质结构。我们利用ODC过表达的培养细胞以及K6/ODC和ODC/Ras转基因小鼠模型（其中ODC过表达靶向毛囊）来评估多胺对组蛋白和其他蛋白质乙酰化的影响。研究发现ODC过表达会改变内在组蛋白乙酰转移酶（HAT）和去乙酰化酶活性以及组蛋白乙酰化模式。ODC转基因小鼠皮肤和肿瘤中表现出的高HAT活性可能部分归因于增强的p300/CREB结合蛋白（CBP）相关HAT活性以及60 kDa Tat相互作用蛋白（Tip60）HAT蛋白异构体水平的增加。在ODC小鼠皮肤和肿瘤中检测到Tip60与E2F1以及一组新鉴定的Tip60相互作用转录因子之间的关联改变，这意味着多胺对Tip60调节的基因表达有新的调节作用。多胺对HAT酶的影响也会影响非组蛋白的乙酰化状态。皮肤中ODC的过表达是肿瘤抑制蛋白p53乙酰化的一种新刺激——p53是p300/CBP和Tip60的共同作用靶点——同时与下游靶基因的结合增加且转录增强。未来的挑战将是阐明多胺影响调节蛋白质乙酰化和基因转录以促进癌症的酶的多种机制。
