Marlene & Stewart Greenebaum Cancer Center, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Epigenomics. 2011 Apr;3(2):145-55. doi: 10.2217/epi.11.12.
Normal cells are up to ten times more resistant to histone deacetylase inhibitors (HDACis)-induced cell death compared with transformed cells. The molecular processes underlying this selectivity for cancer cells are still not well understood. Although a differential response to oxidative stress and capacity to repair damaged DNA have been described in some systems, these cannot fully account for the sensitivity of cancer cells to HDACis since the heterogeneity of cancer cells prompts differential sensitivities to reactive oxygen species and generates a panoply of defective DNA repair mechanisms within given histologies, cancer cell lines and tumor xenografts. It seems also unlikely that the influence of HDACis on cancer treatments reside primarily on gene transcription, since gene-expression profiling aimed at defining correlation with response to HDACis in cancer cells indicates that less than 5% to approximately 20% of transcribed genes are altered by HDACis treatment. Moreover, the altered genes vary from cell line to cell line and between different HDACis. Therefore, no consistent picture of a target(s) or pathway(s) modulated by HDACis has emerged. One consistent parameter that has however been observed in peripheral blood mononuclear cells of patients treated with HDACi is the accumulation of acetylated histones. Because one of the primary functions of histone acetylation is to increase chromatin accessibility, this article will explore the possibility that intrinsic molecular and structural characteristics of cancer cells provide a selective advantage for HDACis sensitivity.
与转化细胞相比，正常细胞对组蛋白去乙酰化酶抑制剂 (HDACi) 诱导的细胞死亡的抗性高达十倍。导致这种癌细胞选择性的分子过程仍未得到很好的理解。尽管在一些系统中已经描述了对氧化应激的不同反应和修复受损 DNA 的能力，但这些并不能完全解释癌细胞对 HDACi 的敏感性，因为癌细胞的异质性导致对活性氧的不同敏感性，并在给定的组织学、癌细胞系和肿瘤异种移植中产生多种有缺陷的 DNA 修复机制。似乎 HDACi 对癌症治疗的影响主要不在于基因转录，因为旨在确定与癌细胞中 HDACi 反应相关性的基因表达谱表明，不到 5%到大约 20%的转录基因被 HDACi 治疗改变。此外，改变的基因因细胞系而异，并且在不同的 HDACi 之间也不同。因此，尚未出现由 HDACi 调节的靶标或途径的一致图像。然而，在接受 HDACi 治疗的患者的外周血单核细胞中观察到一个一致的参数是乙酰化组蛋白的积累。由于组蛋白乙酰化的主要功能之一是增加染色质可及性，本文将探讨癌细胞内在的分子和结构特征为 HDACi 敏感性提供选择性优势的可能性。
