Children's Brain Tumor Research Centre, Medical School, University of Nottingham, Nottingham, United Kingdom.
Mol Cancer Ther. 2010 Sep;9(9):2568-81. doi: 10.1158/1535-7163.MCT-10-0272. Epub 2010 Jul 19.
Aberrant epigenetic regulation of gene expression contributes to tumor initiation and progression. Studies from a plethora of hematologic and solid tumors support the use of histone deacetylase inhibitors (HDACi) as potent anticancer agents. However, the mechanism of HDACi action with respect to the temporal order of induced cellular events is unclear. The present study investigates the anticancer effects of the HDACi trichostatin A in high-grade childhood brain tumor cells. Acute exposure to trichostatin A resulted in marked inhibition of cell proliferation, an increase in the proportion of G(2)-M cells, activation of H2A.X, and subsequent induction of apoptosis in the majority of cell lines. These phenotypic effects were associated with abrogation of telomerase activity and human telomerase reverse transcriptase downregulation in the majority of cell lines. In contrast, no cytotoxicity was observed in primary ependymal cells with respect to cilia function. Thus, inhibition of histone deacetylases leads to antiproliferative and proapoptotic effects in childhood brain tumor cells, likely to involve altered chromatin regulation at the human telomerase reverse transcriptase promoter.
基因表达的异常表观遗传调控导致肿瘤的发生和发展。来自大量血液系统肿瘤和实体瘤的研究支持组蛋白去乙酰化酶抑制剂（HDACi）作为有效的抗癌药物。然而，HDACi 作用的机制，关于诱导细胞事件的时间顺序尚不清楚。本研究探讨了 HDACi 曲古抑菌素 A 在高级别儿童脑肿瘤细胞中的抗癌作用。急性暴露于曲古抑菌素 A 导致细胞增殖明显抑制，G2-M 期细胞比例增加，H2A.X 激活，并随后诱导大多数细胞系凋亡。这些表型效应与大多数细胞系中端粒酶活性和人端粒酶逆转录酶下调有关。相比之下，初级室管膜细胞的纤毛功能没有观察到细胞毒性。因此，组蛋白去乙酰酶的抑制导致儿童脑肿瘤细胞的抗增殖和促凋亡作用，可能涉及到人端粒酶逆转录酶启动子处染色质调控的改变。
