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Histone Signatures Predict Therapeutic Efficacy in Breast Cancer.
IEEE Open Journal of Engineering in Medicine and Biology ( IF 2.7 ) Pub Date : 2020-01-17 , DOI: 10.1109/ojemb.2020.2967105
Shamim A Mollah 1 , Shankar Subramaniam 2
Affiliation  

Objective: Regulatory abnormalities caused by chromatin modifications are being increasingly recognized as contributors to cancer. While many molecularly targeted drugs have the potential to revert these modifications, their precise mechanism of action in cellular reprogramming is not known. Methods: To address this, we introduce an integrated phosphoprotein-histone-drug network (iPhDNet) approach to generate "global chromatin fingerprints of histone signatures." The method integrates proteomic/phosphoproteomic, transcriptomic and regulatory genomic data to provide a causal mechanistic network and histone signatures of drug response. Results: We demonstrate the utility of iPhDNet in identifying H3K27me3K36me3 histone mark as a key fingerprint of response, mediated by chromatin remodelers BRD4, NSD3, EZH2, and a proto-oncogene MYC when treated with CDK inhibitors. Conclusions: We construct a regulatory network of breast cancer response to treatment and show that histone H3K27me3K36me3 status changes, driven by the BRD4/MYC pathway, upon treatment with drugs are hallmarks of response to treatment.

中文翻译:

组蛋白特征预测乳腺癌的治疗效果。

目的:由染色质修饰引起的调节异常越来越被认为是癌症的诱因。虽然许多分子靶向药物有可能逆转这些修饰,但它们在细胞重编程中的确切作用机制尚不清楚。方法:为了解决这个问题,我们引入了一种集成的磷蛋白-组蛋白-药物网络 (iPhDNet) 方法来生成“组蛋白特征的全局染色质指纹”。该方法整合了蛋白质组学/磷酸化蛋白质组学、转录组学和调控基因组数据,以提供药物反应的因果机制网络和组蛋白特征。结果:我们证明了 iPhDNet 在识别 H3K27me3K36me3 组蛋白标记作为响应的关键指纹方面的效用,由染色质重塑剂 BRD4、NSD3、EZH2、和原癌基因 MYC 用 CDK 抑制剂治疗时。结论:我们构建了乳腺癌对治疗反应的调节网络,并表明在药物治疗后由 BRD4/MYC 通路驱动的组蛋白 H3K27me3K36me3 状态变化是治疗反应的标志。
更新日期:2020-01-17
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