Histone deacetylase inhibitor-mediated cell death is distinct from its global effect on chromatin.
Histone deacetylase inhibitor-mediated cell death is distinct from its global effect on chromatin.
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DOI：
10.1016/j.molonc.2014.05.001
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发表时间：
2014-12
影响因子：
6.6
通讯作者：
Bates SE
中科院分区：
文献类型：
--
作者：
Luchenko VL;Litman T;Chakraborty AR;Heffner A;Devor C;Wilkerson J;Stein W;Robey RW;Bangiolo L;Levens D;Bates SE
罗米地辛和伏立诺他是组蛋白脱乙酰酶抑制剂（HDACis），其在T细胞淋巴瘤中具有活性，但在实体瘤中没有获得牵引力。为了更深入地了解HDACi功效的机制，我们系统地调查了具有不同分子表型的十九种细胞系，比较了等效剂量的罗米地辛和伏立诺他。通过反相蛋白质组学阵列（RPPA）测量H3K9和H4K8沿着的乙酰化以及其他22种组蛋白赖氨酸乙酰化和甲基化修饰，并与生长抑制（IC 50）和细胞周期停滞进行比较。通常用于评估HDACi效应的这些测定显示，响应HDACi的特定赖氨酸残基的乙酰化和甲基化在细胞系中是一致的，并且与药物敏感性无关。使用更能反映临床暴露的治疗持续时间，在6小时药物暴露后通过膜联蛋白染色检测到的细胞死亡鉴定了对HDAC抑制明显更敏感的细胞系亚组，包括T细胞淋巴瘤系。动力学参数（Km值）测定赖氨酸乙酰化和细胞周期的数据，并与HDACi暴露后，但没有参数与细胞死亡相关。对细胞存活信号传导的影响随分子表型而变化。这项研究表明，细胞对HDACis的反应可以被视为两种不同的效应：染色质效应和细胞死亡效应。所有的细胞都经历乙酰化，这是细胞死亡所必需的，但不是充分的。未引发细胞凋亡的细胞不会对改变的组蛋白乙酰化的影响产生细胞死亡的反应。观察到的不同凋亡反应反映了HDACi治疗的可变临床结果。这些观察结果应该改变我们开发利用HDACis双重活性的治疗策略的方法。
Romidepsin and vorinostat are histone deacetylase inhibitors (HDACis) that have activity in T-cell lymphomas, but have not gained traction in solid tumors. To gain deeper insight into mechanisms of HDACi efficacy, we systematically surveyed nineteen cell lines with different molecular phenotypes, comparing romidepsin and vorinostat at equipotent doses. Acetylation at H3K9 and H4K8 along with 22 other histone lysine acetylation and methylation modifications were measured by reverse phase proteomics array (RPPA), and compared with growth inhibition (IC50), and cell cycle arrest. These assays typically used to assess HDACi effect showed that acetylation and methylation of specific lysine residues in response to HDACis was consistent across cell lines, and not related to drug sensitivity. Using a treatment duration more reflective of the clinical exposure, cell death detected by annexin staining following a 6 hour drug exposure identified a subset of cell lines, including the T-cell lymphoma line, that was markedly more sensitive to HDAC inhibition. Kinetic parameters (Km values) were determined for lysine acetylation and for cell cycle data and were themselves correlated following HDACi exposure, but neither parameter correlated with cell death. The impact on cell survival signaling varied with the molecular phenotype. This study suggests that cellular response to HDACis can be viewed as two distinct effects: a chromatin effect and a cell death effect. All cells undergo acetylation, which is necessary but not sufficient for cell death. Cells not primed for apoptosis will not respond with cell death to the impact of altered histone acetylation. The divergent apoptotic responses observed reflect the variable clinical outcome of HDACi treatment. These observations should change our approach to the development of therapeutic strategies that exploit the dual activities of HDACis.