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Identification of Jun loss promotes resistance to histone deacetylase inhibitor entinostat through Myc signaling in luminal breast cancer
6月缺失的鉴定促进了 luminal 乳腺癌中通过 Myc 信号途径对组蛋白去乙酰化酶抑制剂 entinostat 的抵抗

摘要

Abstract Background Based on promising phase II data, the histone deacetylase inhibitor entinostat is in phase III trials for patients with metastatic estrogen receptor-positive breast cancer. Predictors of sensitivity and resistance, however, remain unknown. Methods A total of eight cell lines and nine mouse models of breast cancer were treated with entinostat. Luminal cell lines were treated with or without entinostat at their IC50 doses, and MMTV/Neu luminal mouse tumors were untreated or treated with entinostat until progression. We investigated these models using their gene expression profiling by microarray and copy number by arrayCGH. We also utilized the network-based DawnRank algorithm that integrates DNA and RNA data to identify driver genes of resistance. The impact of candidate drivers was investigated in The Cancer Genome Atlas and METABRIC breast cancer datasets. Results Luminal models displayed enhanced sensitivity to entinostat as compared to basal-like or claudin-low models. Both in vitro and in vivo luminal models showed significant downregulation of Myc gene signatures following entinostat treatment. Myc gene signatures became upregulated on tumor progression in vivo and overexpression of Myc conferred resistance to entinostat in vitro. Further examination of resistance mechanisms in MMTV/Neu tumors identified a portion of mouse chromosome 4 that had DNA copy number loss and low gene expression. Within this region, Jun was computationally identified to be a driver gene of resistance. Jun knockdown in cell lines resulted in upregulation of Myc signatures and made these lines more resistant to entinostat. Jun-deleted samples, found in 17–23% of luminal patients, had significantly higher Myc signature scores that predicted worse survival. Conclusions Entinostat inhibited luminal breast cancer through Myc signaling, which was upregulated by Jun DNA loss to promote resistance to entinostat in our models. Jun DNA copy number loss, and/or high MYC signatures, might represent biomarkers for entinostat responsiveness in luminal breast cancer.

译文

背景基于有希望的 II 期数据,组蛋白去乙酰化酶抑制剂 entinostat 正在对转移性雌激素受体阳性乳腺癌患者进行 III 期试验。然而,敏感性和抗性的预测因素仍然未知。方法用恩他诺治疗 8 个乳腺癌细胞株和 9 个小鼠模型。Luminal 细胞系在 IC50 剂量下用或不用 entinostat 处理,MMTV/Neu luminal 小鼠肿瘤未处理或用 entinostat 处理,直到进展。我们使用微阵列的基因表达谱和 arrayCGH 的拷贝数研究了这些模型。我们还利用了基于网络的 DawnRank 算法,该算法整合了 DNA 和 RNA 数据来识别抗性的驱动基因。在癌症基因组图谱和代谢乳腺癌数据集中研究了候选驱动因素的影响。结果与基底样或 claudin-low 模型相比,Luminal 模型对 entinostat 的敏感性增强。在体外和体内的管腔模型都显示出 entinostat 治疗后的 Myc 基因特征的显著下调。在体内肿瘤进展过程中,Myc 基因标记上调,而在体外,Myc 的过表达赋予了对 entinostat 的抗性。进一步检查 MMTV/Neu 肿瘤的耐药机制,发现小鼠 4 号染色体的一部分存在 DNA 拷贝数丢失和低基因表达。在这个区域内,6月被计算确定为抗性的驱动基因。6月,细胞系中的击倒导致了 Myc 信号的上调,并使这些细胞系对 entinostat 更具抗性。6月-在 17-23% 的 luminal 患者中发现的删除样本,其 Myc 特征分数明显较高,预示着更差的存活率。结论 Entinostat 通过在我们的模型中通过 6月 DNA 丢失而上调的 Myc 信号抑制 luminal 乳腺癌,以促进对 entinostat 的抵抗。6月 DNA 拷贝数丢失,和/或高 MYC 标记,可能代表 luminal 乳腺癌中 entinostat 反应性的生物标志物。

Histone deacetylase

肿瘤 蛋白酶 临床研究术语
概述  :  

组蛋白去乙酰化酶(HDAC)是一类蛋白酶,对染色体的结构修饰和基因表达调控发挥着重要的作用。一般情况下,组蛋白的乙酰化有利于DNA与组蛋白把具体的解离,核小体结构松弛,从而使各种转录因子和协同转录因子能与DNA结合位点特异性结合,激活基因的转录。在细胞核内,组蛋白乙酰化与去乙酰化过程处于动态平衡,并由组蛋白乙酰化转移酶和组蛋白去乙酰化酶共同调控。组蛋白乙酰化转移酶将乙酰辅酶A的乙酰基转移到组蛋白氨基末端特定的赖氨酸残基上,HDAC使组蛋白去乙酰化,与带负电荷的DNA紧密结合,染色质致密卷曲,

Histone   英 /'hɪstəʊn/   美 /'hɪston/

释    义   n. [生化] 组蛋白

例    句   The changes of epigenetics such as DNA methylation and histone modification can regulate the expression of genes and play an important role in the development of tumors. 表观遗传学改变,如DNA甲基化和组蛋白修饰改变可以调控基因的表达,在肿瘤的发生和发展中可能起关键作用。

 

Deacetylase

释    义   n. 脱乙酰酶;去乙酰酶

例    句   Indeed, HDAC6 deacetylates various substrates including α-tubulin and HSP90α, and is involved in protein trafficking and degradation, cell shape and migration. 事实上,HDAC6可以α-微管蛋白和HSP90α进行去乙酰化,与蛋白质转运、降解、细胞形状和迁移都有关系。

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