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首页> 外文期刊>Oncology reports >Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells
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Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

机译：表观遗传二价标记允许HDAC和PARP抑制剂对乳腺癌细胞TXNIP表达的协同作用

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摘要

Studies on stem cell differentiation led to the identification of paused genes, characterized by the contemporary presence of both activator and repressor epigenetic markers (bivalent marking). TXNIP is an oncosuppressor gene the expression of which was reduced in breast cancer. In the present study, we evaluated whether the concept of epigenetic bivalent marking can be applied to TXNIP gene in breast cancer cells. Using chromatin immunoprecipitation (ChIP), three histone modifications were investigated: two associated with transcriptional activation, lysines 9-14 acetylation of H3 histone (H3K9K14ac) and lysine 4 trimethylation of H3 histone (H3K4me3), and one associated with transcriptional silencing, lysine 27 trimethylation of H3 histone (H3K27me3). According to the bivalent marking model, TXNIP gene appears to be paused in MDA157 cells (markers of active and repressed transcription are present), but are definitively silenced in MDA468 cells (presence of only markers of transcription repression). This was proven by evaluating TXNIP mRNA and protein levels after the treatment of cell lines with a histone deacetylase inhibitor (SAHA) and a poly-ADPribose polymerases inhibitor (PJ34). In MDA157 cells, SAHA and PJ34 showed a synergistic effect: a large increment was observed in TXNIP mRNA and protein levels. By contrast, in MDA468 cells, synergy between the two compounds was not observed. Therefore, the pausing epigenetic signature was permissive for synergy between SAHA and PJ34 on TXNIP gene expression. The synergy between SAHA and PJ34 on TXNIP expression was associated with variation in cell viability and apoptosis. In MDA157 cells, but not in MDA468 cells, combined treatment of SAHA and PJ34 induced a decrease in cell viability and an increase of apoptosis. Thus, our data support the hypothesis that TXNIP is an effective target for the treatment of breast cancer.
机译：干细胞分化的研究导致了被暂停基因的鉴定，其特征是激活剂和阻遏物表观遗传标记物（二价标记物）的当代存在。 TXNIP是一种抑癌基因，在乳腺癌中其表达降低。在本研究中，我们评估了表观遗传二价标记的概念是否可以应用于乳腺癌细胞中的TXNIP基因。使用染色质免疫沉淀（ChIP），研究了三个组蛋白修饰：两个与转录激活相关，H3组蛋白的赖氨酸9-14乙酰化（H3K9K14ac）和H3组蛋白的赖氨酸4三甲基化（H3K4me3），一个与转录沉默相关的赖氨酸27 H3组蛋白（H3K27me3）的三甲基化。根据二价标记模型，TXNIP基因似乎在MDA157细胞中被暂停（存在活跃和被抑制的转录标记），但在MDA468细胞中被确定地沉默（仅存在转录抑制标记）。通过用组蛋白脱乙酰基酶抑制剂（SAHA）和聚ADPribose聚合酶抑制剂（PJ34）处理细胞系后评估TXNIP mRNA和蛋白质水平，证明了这一点。在MDA157细胞中，SAHA和PJ34表现出协同作用：在TXNIP mRNA和蛋白质水平上观察到较大的增加。相反，在MDA468细胞中，未观察到两种化合物之间的协同作用。因此，暂停表观遗传签名允许SAHA和PJ34在TXNIP基因表达上的协同作用。 SAHA和PJ34在TXNIP表达上的协同作用与细胞活力和凋亡的变化有关。在MDA157细胞中，而非MDA468细胞中，SAHA和PJ34的联合治疗诱导细胞活力降低和细胞凋亡增加。因此，我们的数据支持TXNIP是治疗乳腺癌的有效靶点这一假设。

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