Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics.
Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics.
复制标题
DOI：
10.1038/s41598-017-00143-6
复制
发表时间：
2017-03-15
影响因子：
4.6
通讯作者：
Agarwal PK
中科院分区：
文献类型：
--
作者：
Li QQ;Hao JJ;Zhang Z;Krane LS;Hammerich KH;Sanford T;Trepel JB;Neckers L;Agarwal PK
热休克蛋白90 （HSP90）抑制是一种有吸引力的癌症治疗策略。几种HSP90抑制剂在临床肿瘤试验中显示出有希望的效果。然而，对HSP90抑制介导的膀胱癌治疗知之甚少。在这里，我们报告了一项定量蛋白质组学研究，评估了膀胱癌中蛋白表达和组蛋白翻译后修饰（PTMs）对HSP90抑制的反应。我们发现5种HSP90抑制剂（AUY922, ganetespib, SNX2112， AT13387和CUDC305）以剂量和时间依赖的方式有效抑制膀胱癌5637细胞的增殖。我们的蛋白质组学研究量化了518个双重上调和811个双重下调的蛋白，这些蛋白在AUY922和ganetespib处理中都是常见的。生物信息学分析显示，这些差异表达蛋白参与多种细胞过程和酶调节的信号通路，包括染色质修饰和细胞死亡相关通路。此外，定量蛋白质组学研究在AUY922和ganetespib处理的5637个细胞中鉴定出14种核心组蛋白上有93个标记的PTMs，包括34个新的组蛋白标记，包括丁基化、瓜氨酸化、2-羟基异丁基化、甲基化、o - glcn酰化、丙酰化和琥珀酰化。总之，本研究概述了膀胱癌细胞对HSP90抑制剂治疗的反应中蛋白质组学变化与组蛋白PTMs之间的关系，从而加强了对HSP90抑制剂介导的膀胱癌治疗方法的理解。
Heat shock protein 90 (HSP90) inhibition is an attractive strategy for cancer treatment. Several HSP90 inhibitors have shown promising effects in clinical oncology trials. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we report a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder carcinoma in response to HSP90 inhibition. We show that 5 HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells in a dose- and time-dependent manner. Our proteomic study quantified 518 twofold up-regulated and 811 twofold down-regulated proteins common to both AUY922 and ganetespib treatment. Bioinformatic analyses revealed that those differentially expressed proteins were involved in multiple cellular processes and enzyme-regulated signaling pathways, including chromatin modifications and cell death-associated pathways. Furthermore, quantitative proteome studies identified 14 types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, methylation, O-GlcNAcylation, propionylation, and succinylation in AUY922- and ganetespib-treated 5637 cells. Together, this study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder carcinoma cells, and thus intensifies the understanding of HSP90 inhibition-mediated bladder cancer therapeutics.