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心力衰竭药物普斯可林 A 通过赖氨酸乙酰化的全球缺失靶向 MYC 过表达白血病。

Heart failure drug proscillaridin A targets MYC overexpressing leukemia through global loss of lysine acetylation.

机构信息

Département de pharmacologie et physiologie, Université de Montréal, Montréal, (Québec), Canada.

Sainte-Justine University Hospital Research Center (7.17.020), 3175, Chemin de la Côte-Sainte-Catherine, Montréal, (Québec), H3T 1C5, Canada.

出版信息

J Exp Clin Cancer Res. 2019 Jun 13;38(1):251. doi: 10.1186/s13046-019-1242-8.

Abstract

BACKGROUND

Cardiac glycosides are approved for the treatment of heart failure as Na/K pump inhibitors. Their repurposing in oncology is currently investigated in preclinical and clinical studies. However, the identification of a specific cancer type defined by a molecular signature to design targeted clinical trials with cardiac glycosides remains to be characterized. Here, we demonstrate that cardiac glycoside proscillaridin A specifically targets MYC overexpressing leukemia cells and leukemia stem cells by causing MYC degradation, epigenetic reprogramming and leukemia differentiation through loss of lysine acetylation.

METHODS

Proscillaridin A anticancer activity was investigated against a panel of human leukemia and solid tumor cell lines with different MYC expression levels, overexpression in vitro systems and leukemia stem cells. RNA-sequencing and differentiation studies were used to characterize transcriptional and phenotypic changes. Drug-induced epigenetic changes were studied by chromatin post-translational modification analysis, expression of chromatin regulators, chromatin immunoprecipitation, and mass-spectrometry.

RESULTS

At a clinically relevant dose, proscillaridin A rapidly altered MYC protein half-life causing MYC degradation and growth inhibition. Transcriptomic profile of leukemic cells after treatment showed a downregulation of genes involved in MYC pathways, cell replication and an upregulation of hematopoietic differentiation genes. Functional studies confirmed cell cycle inhibition and the onset of leukemia differentiation even after drug removal. Proscillaridin A induced a significant loss of lysine acetylation in histone H3 (at lysine 9, 14, 18 and 27) and in non-histone proteins such as MYC itself, MYC target proteins, and a series of histone acetylation regulators. Global loss of acetylation correlated with the rapid downregulation of histone acetyltransferases. Importantly, proscillaridin A demonstrated anticancer activity against lymphoid and myeloid stem cell populations characterized by MYC overexpression.

CONCLUSION

Overall, these results strongly support the repurposing of proscillaridin A in MYC overexpressing leukemia.

摘要

背景

强心苷作为 Na/K 泵抑制剂被批准用于心力衰竭的治疗。它们在肿瘤学中的再利用目前正在临床前和临床研究中进行研究。然而,确定一种由分子特征定义的特定癌症类型,以设计针对强心苷的靶向临床试验,仍有待研究。在这里,我们证明强心苷普罗沙林 A 通过导致 MYC 降解、表观遗传重编程和白血病分化,通过赖氨酸乙酰化丧失,特异性靶向 MYC 过表达的白血病细胞和白血病干细胞。

方法

用不同 MYC 表达水平、体外过表达系统和白血病干细胞的一系列人白血病和实体肿瘤细胞系来研究普罗沙林 A 的抗癌活性。RNA 测序和分化研究用于表征转录和表型变化。通过染色质翻译后修饰分析、染色质调节因子表达、染色质免疫沉淀和质谱研究来研究药物诱导的表观遗传变化。

结果

在临床相关剂量下,普罗沙林 A 迅速改变 MYC 蛋白半衰期,导致 MYC 降解和生长抑制。治疗后白血病细胞的转录组谱显示,参与 MYC 途径、细胞复制的基因下调,造血分化基因上调。功能研究证实,即使在药物去除后,细胞周期也会受到抑制,白血病分化也会开始。普罗沙林 A 导致组蛋白 H3(赖氨酸 9、14、18 和 27)和非组蛋白蛋白(如 MYC 本身、MYC 靶蛋白和一系列组蛋白乙酰化调节剂)中的赖氨酸乙酰化显著丧失。总体上,乙酰化丢失与组蛋白乙酰转移酶的快速下调相关。重要的是,普罗沙林 A 对 MYC 过表达的淋巴样和髓样干细胞群表现出抗癌活性。

结论

总的来说,这些结果强烈支持将普罗沙林 A 重新用于 MYC 过表达的白血病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842f/6563382/3127508460df/13046_2019_1242_Fig1_HTML.jpg

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