Introduction

A large subset of diffusely infiltrative gliomas contains a gain-of-function mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2^mut) which produces 2-hydroxglutarate, an inhibitor of α-ketoglutarate-dependent DNA demethylases, thereby inducing widespread DNA and histone methylation. Because histone deacetylase (HDAC) enzymes are localized to methylated chromatin via methyl-binding domain proteins, IDH1/2^mut gliomas may be more dependent on HDAC activity, and therefore may be more sensitive to HDAC inhibitors.

Methods

Six cultured patient-derived glioma cell lines, IDH1^wt (n = 3) and IDH1^mut (n = 3), were treated with an FDA-approved HDAC inhibitor, panobinostat. Cellular cytotoxicity and proliferation assays were conducted by flow cytometry. Histone modifications and cell signaling pathways were assessed using immunoblot and/or ELISA.

Results

IDH1^mut gliomas exhibited marked upregulation of genes associated with the HDAC activity. Glioma cell cultures bearing IDH1^mut were significantly more sensitive to the cytotoxic and antiproliferative effects of panobinostat, compared to IDH1^wt glioma cells. Panobinostat caused a greater increase in acetylation of the histone residues H3K14, H3K18, and H3K27 in IDH1^mut glioma cells. Another HDAC inhibitor, valproic acid, was also more effective against IDH1^mut glioma cells.

Conclusion

These data suggest that IDH1^mut gliomas may be preferentially sensitive to HDAC inhibitors. Further, IDH1^mut glioma cultures showed enhanced accumulation of acetylated histone residues in response to panobinostat treatment, suggesting a direct epigenetic mechanism for this sensitivity. This provides a rationale for further exploration of HDAC inhibitors against IDH1^mut gliomas.

中文翻译：

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IDH1 突变型胶质瘤优先对 HDAC 抑制剂 panobinostat 敏感

介绍

大部分弥漫性浸润性神经胶质瘤包含异柠檬酸脱氢酶 1 或 2 (IDH1/2 ^mut ) 的功能获得性突变，该突变产生 2-羟基戊二酸，一种 α-酮戊二酸依赖性 DNA 去甲基化酶的抑制剂，从而诱导广泛的 DNA 和组蛋白甲基化。由于组蛋白去乙酰化酶 (HDAC) 酶通过甲基结合域蛋白定位于甲基化染色质，IDH1/2 ^mut胶质瘤可能更依赖于 HDAC 活性，因此可能对 HDAC 抑制剂更敏感。

方法

用 FDA 批准的 HDAC 抑制剂 panobinostat 治疗六种培养的患者来源的神经胶质瘤细胞系 IDH1 ^wt (n = 3) 和 IDH1 ^{mut (n = 3)。}通过流式细胞术进行细胞毒性和增殖测定。使用免疫印迹和/或 ELISA 评估组蛋白修饰和细胞信号通路。

结果

IDH1 ^mut胶质瘤表现出与 HDAC 活性相关的基因的显着上调。^{与 IDH1 wt}胶质瘤细胞相比，携带 IDH1 ^mut的胶质瘤细胞培养物对 panobinostat的细胞毒性和抗增殖作用明显更敏感。Panobinostat 导致 IDH1 ^mut神经胶质瘤细胞中组蛋白残基 H3K14、H3K18 和 H3K27 乙酰化的更大增加。另一种 HDAC 抑制剂丙戊酸对 IDH1 ^mut胶质瘤细胞也更有效。

结论

这些数据表明 IDH1 ^mut神经胶质瘤可能对 HDAC 抑制剂优先敏感。此外，IDH1 ^mut神经胶质瘤培养物显示出乙酰化组蛋白残基对 panobinostat 治疗的反应增强，表明这种敏感性的直接表观遗传机制。这为进一步探索针对 IDH1 ^mut胶质瘤的 HDAC 抑制剂提供了依据。