Histone deacetylase inhibitor, panobinostat, exerts anti-proliferative effect with partial normalization from aberrant epigenetic states on granulosa cell tumor cell lines.
Histone deacetylase inhibitor, panobinostat, exerts anti-proliferative effect with partial normalization from aberrant epigenetic states on granulosa cell tumor cell lines.
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组蛋白去乙酰化酶抑制剂panobinostat在颗粒细胞肿瘤细胞系中发挥抗增殖作用，并从异常表观遗传状态部分正常化。
DOI：
10.1371/journal.pone.0271245
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Shimoya, Koichiro
中科院分区：
文献类型：
--
作者：
Hazama, Yukiko;Tsujioka, Takayuki;Kitanaka, Akira;Tohyama, Kaoru;Shimoya, Koichiro
不能手术或晚期颗粒细胞瘤（GCTs）患者的预后仍然很差，因此建立新的治疗策略至关重要。在这里，我们研究了组蛋白去乙酰化酶抑制剂帕比司他（PS）对两种GCT细胞系（KGN和COV 434）的体外作用。GCT细胞系被发现是敏感的PS处理，它主要通过凋亡抑制细胞生长。在细胞周期分析中，PS仅降低GCT细胞S期比例。PS与去泛素化酶抑制剂VLX 1570的联合治疗增强了p21、裂解的PARP、裂解的半胱天冬酶-9、血红素加氧酶-1的表达以及组蛋白H4和α-微管蛋白的乙酰化，导致对KGN和COV 434的叠加抗增殖作用。基因集富集分析显示，PS处理抑制DNA复制或细胞周期相关基因表达，导致化疗细胞死亡，此外，该处理诱导粘附连接基因集向标准化方向活化以及神经元相关基因集活化，这可能意味着由于KGN细胞中HDAC抑制剂的表观遗传修饰而导致的意外分化潜力。暴露于PS的KGN和COV 434细胞增加了E-cadherin的表达，E-cadherin是定量RT-PCR和免疫印迹分析中与粘附连接相关的主要调节因子之一。在本研究中，我们指出了HDAC抑制剂用于治疗GCT的新的治疗可用性的基础，并将进行进一步的研究。
The prognosis of the patients with inoperable or advanced granulosa cell tumors (GCTs) is still poor, and therefore it is important to establish a novel treatment strategy. Here we investigated the in vitro effects of a histone deacetylase inhibitor, panobinostat (PS) on two GCT cell lines (KGN and COV434). GCT cell lines were found to be susceptible to PS treatment and it inhibited cell growth mainly by apoptosis. In cell cycle analysis, PS reduced only the ratio of S phase in GCT cell lines. Combined treatment of PS with a deubiquitinase inhibitor, VLX1570 enhanced the expression of p21, cleaved PARP, cleaved caspase-9, heme oxygenase-1, and the acetylation of histone H4 and α-tubulin, leading to an additive anti-proliferative effect on KGN and COV434. The gene set enrichment analysis revealed that PS treatment suppressed DNA replication- or cell cycle-related gene expression which led to chemotherapeutic cell death and in addition, this treatment induced activation of the gene set of adherens junction towards a normalized direction as well as activation of neuron-related gene sets that might imply unexpected differentiation potential due to epigenetic modification by a HDAC inhibitor in KGN cells. Exposure of KGN and COV434 cells to PS increased the expression of E-cadherin, one of the principal regulators associated with adherens junction in quantitative RT-PCR and immunoblotting analysis. In the present study, we indicate a basis of a novel therapeutic availability of a HDAC inhibitor for the treatment of GCTs and further investigations will be warranted.
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影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
DOI：
10.1083/jcb.143.7.1883
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnston JA;Ward CL;Kopito RR
通讯作者：
Kopito RR
影响因子：
20.3
作者：
Catley, Laurence;Weisberg, Ellen;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
5.7
作者：
Hui, Kwai Fung;Lam, Benjamin H. W.;Chiang, Alan K. S.
通讯作者：
Chiang, Alan K. S.
影响因子：
3.4
作者：
Budman, Daniel R.;Tai, Julia;John, Veena
通讯作者：
John, Veena