Targeting histones for degradation in cancer cells as a novel strategy in cancer treatment
Targeting histones for degradation in cancer cells as a novel strategy in cancer treatment
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靶向组蛋白在癌细胞中降解作为癌症治疗的新策略
DOI：
10.1007/s11427-018-9391-7
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Xiaobo Qiu
中科院分区：
文献类型：
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作者：
Yesheng Yin;Qianqian Zhu;Tianxia Jiang;Libin Fan;Xiaobo Qiu
组蛋白去乙酰化酶（HDAC）抑制剂和dna损伤联合治疗的抗癌疗法正在积极进行临床研究，但其潜在机制尚不清楚。组蛋白稳态对基因组稳定性、转录准确性、DNA修复过程、衰老和生存至关重要。我们之前已经证明，HDAC抑制剂trichostatin A （TSA）可以促进γ辐射或dna烷基化剂甲基甲烷磺酸盐（MMS）诱导的非癌细胞（包括小鼠精细胞和胚胎成纤维细胞系）核心组蛋白的降解。在本研究中，我们发现TSA和MMS联合作用对培养的癌细胞具有累加效应，但对癌细胞核心组蛋白的降解具有协同作用。然后，我们分析了其他HDAC抑制剂的各种组合，包括亚甲基苯胺羟肟酸和丙戊酸钠，与MMS或其他dna损伤剂，包括依托泊苷和喜树碱。大多数这些联合处理诱导细胞死亡，但所有测试的组合诱导核心组蛋白的降解协同。同时，我们发现细胞周期阻滞可能不是TSA和MMS联合治疗的主要结果。鉴于癌症的临床治疗与HDAC抑制剂和dna损伤方法联合通常显示出协同效应，组蛋白降解可能比其他参数（如细胞死亡和细胞周期阻滞）更准确地反映了这些联合治疗在临床应用中的协同效应。因此，我们的研究可能表明，核心组蛋白的降解可以作为开发癌症治疗的新靶点。
The anticancer therapies with the joint treatment of a histone deacetylase (HDAC) inhibitor and a DNA-damaging approach are actively under clinical investigations, but the underlying mechanism is unclear. Histone homeostasis is critical to genome stability, transcriptional accuracy, DNA repair process, senescence, and survival. We have previously demonstrated that the HDAC inhibitor, trichostatin A (TSA), could promote the degradation of the core histones induced by γ-radiation or the DNAalkylating agent methyl methanesulfonate (MMS) in non-cancer cells, including mouse spermatocyte and embryonic fibroblast cell lines. In this study, we found that the joint treatment by TSA and MMS induced the death of the cultured cancer cells with an additive effect, but induced degradation of the core histones synergistically in these cells. We then analyzed various combinations of other HDAC inhibitors, including suberoylanilide hydroxamic acid and valproate sodium, with MMS or other DNAdamaging agents, including etoposide and camptothecin. Most of these combined treatments induced cell death additively, but all the tested combinations induced degradation of the core histones synergistically. Meanwhile, we showed that cell cycle arrest might not be a primary consequence for the joint treatment of TSA and MMS. Given that clinic treatments of cancers jointly with an HDAC inhibitor and a DNA-damaging approach often show synergistic effects, histone degradation might more accurately underlie the synergistic effects of these joint treatments in clinic applications than other parameters, such as cell death and cell cycle arrest. Thus, our studies might suggest that the degradation of the core histones can serve as a new target for the development of cancer therapies.