Histone acetyltransferase inhibitor II induces apoptosis in glioma cell lines via the p53 signaling pathway.
Histone acetyltransferase inhibitor II induces apoptosis in glioma cell lines via the p53 signaling pathway.
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组蛋白乙酰转移酶抑制剂 II 通过 p53 信号通路诱导胶质瘤细胞系凋亡
DOI：
10.1186/s13046-014-0108-3
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发表时间：
2014-12-19
期刊：
影响因子：
--
通讯作者：
Pan J
中科院分区：
文献类型：
--
作者：
Xu LX;Li ZH;Tao YF;Li RH;Fang F;Zhao H;Li G;Li YH;Wang J;Feng X;Pan J
背景组蛋白乙酰转移酶（HAT）抑制剂可以抑制癌细胞系的增殖并诱导细胞凋亡。新型细胞渗透性 p300/CREB 结合蛋白 (CBP) 选择性 HAT 抑制剂 HATi II 可以减少 HeLa 细胞中组蛋白 H3 乙酰化并诱导染色质浓缩。在这里，我们检查了 HATi II 在神经胶质瘤细胞系中的作用和作用机制。方法使用 CCK-8 测定评估细胞活力。使用流式细胞术进行细胞周期分析。使用膜联蛋白V染色和流式细胞术、Hoechst 33342染色和TUNEL测定来评估细胞凋亡。通过蛋白质印迹评估 caspase-3、caspase-9 和聚 ADP-核糖聚合酶 (PARP) 的表达和裂解。使用双尾学生 t 检验进行统计分析。使用 Arraystar Human 8 x 60 K LncRNA/mRNA 表达阵列分析经 HATi II 或 DMSO 处理的 U251 神经胶质瘤细胞的基因表达谱；使用MEV（多实验视图）集群软件分析数据。对聚类分析中表达谱改变（≥2倍）的基因数据集进行基因本体论和通路分析。结果HATi II以剂量依赖性方式抑制U251、U87、HS683和SHG44细胞的增殖。 HATi II 诱导细胞周期停滞在 G2/M 期，并在 HATi II 处理的 U251 和 SHG44 细胞中诱导显着水平的细胞凋亡、凋亡体形成和 DNA 断裂。 HATi II 诱导 U251 和 SHG44 细胞中 caspase-3、caspase-9 和 PARP 的裂解。在HATi II处理的U251细胞中，965个基因上调，984个基因下调，3492/33327个lncRNA差异表达。 GO分析显示功能已知的差异表达基因参与多种过程；酗酒、p53 信号通路、细胞因子-细胞因子受体相互作用和癌症转录失调是四个最重要的通路。通过定量RT-PCR和Western印迹证实HATi II处理的细胞中p53信号通路相关基因的上调。结论HATi II通过激活p53信号通路，通过caspase依赖性通路抑制人胶质瘤细胞系的增殖并诱导细胞凋亡。 HATi II 作为神经胶质瘤的新型治疗方法值得进一步研究。
BackgroundHistone acetyltransferase (HAT) inhibitors can inhibit proliferation and induce apoptosis in cancer cell lines. The novel cell-permeable p300/CREB-binding protein (CBP)-selective HAT inhibitor HATi II can reduce histone H3 acetylation and induce chromatin condensation in HeLa cells. Here, we examined the effects and mechanism of action of HATi II in glioma cell lines.MethodsCell viability was assessed using the CCK-8 assay. Cell cycle analysis was performed using flow cytometry. Apoptosis was evaluated using Annexin V staining and flow cytometry, Hoechst 33342 staining and the TUNEL assay. Expression and cleavage of caspase-3, caspase-9 and poly ADP-ribose polymerase (PARP) were assessed by Western blotting. Statistical analysis was performed using two-tailed Student’s t-tests. The gene expression profiles of U251 glioma cells treated with HATi II or DMSO were analyzed using the Arraystar Human 8 x 60 K LncRNA/mRNA expression array; data was analyzed using MEV (Multi Experiment View) cluster software. Datasets representing genes with altered expression profiles (≥2-fold) derived from the cluster analyses were subjected to gene ontology and pathway analysis.ResultsHATi II inhibited the proliferation of U251, U87, HS683 and SHG44 cells in a dose-dependent manner. HATi II induced cell cycle arrest at the G2/M phase, and induced significant levels of apoptosis, apoptotic body formation and DNA fragmentation in HATi II-treated U251 and SHG44 cells. HATi II induced cleavage of caspase-3, caspase-9 and PARP in U251 and SHG44 cells. In HATi II-treated U251 cells, 965 genes were upregulated, 984 genes were downregulated and 3492/33327 lncRNAs were differentially expressed. GO analysis showed the differentially expressed genes with known functions are involved in a variety of processes; alcoholism, p53 signaling pathway, cytokine-cytokine receptor interaction and transcriptional mis-regulation in cancer were the four most significant pathways. Upregulation of p53 signaling pathway-related genes in HATi II-treated cells was confirmed by quantitative RT-PCR and Western blotting.ConclusionsHATi II inhibits proliferation and induces apoptosis via the caspase-dependent pathway in human glioma cell lines, possibly by activating the p53 signaling pathway. HATi II deserves further investigation as a novel treatment for glioma.
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DOI：
10.1186/1478-811x-8-31
发表时间：
2010-12-22
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Chaitanya GV;Steven AJ;Babu PP
通讯作者：
Babu PP
影响因子：
4.8
作者：
Monte, M;Benetti, R;Schneider, C
通讯作者：
Schneider, C
影响因子：
3.4
作者：
Lenoci, Alessia;Tomassi, Stefano;Mai, Antonello
通讯作者：
Mai, Antonello
影响因子：
8
作者：
Iyer, N. G.;Xian, J.;Caldas, C.
通讯作者：
Caldas, C.
影响因子：
4.8
作者：
Nicholls, CD;Shields, MA;Beattie, TL
通讯作者：
Beattie, TL