Targeting KDM1A attenuates Wnt/β-catenin signaling pathway to eliminate sorafenib-resistant stem-like cells in hepatocellular carcinoma
Targeting KDM1A attenuates Wnt/β-catenin signaling pathway to eliminate sorafenib-resistant stem-like cells in hepatocellular carcinoma
复制标题
靶向 KDM1A 减弱 Wnt/β-catenin 信号通路以消除肝细胞癌中索拉非尼耐药的干细胞样细胞
DOI：
10.1016/j.canlet.2017.03.038
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发表时间：
2017-07-10
期刊：
影响因子：
9.7
通讯作者：
Chu, Xiaoyuan
中科院分区：
文献类型：
--
作者：
Huang, Mengxi;Chen, Cheng;Chu, Xiaoyuan
酪氨酸激酶抑制剂索拉非尼在晚期肝细胞癌（HCC）患者中的应用经常受到耐药性发展的阻碍，最近已显示耐药性与癌症干细胞（CSC）亚群的出现有关。然而，表观遗传机制，特别是组蛋白翻译后修饰，是否与索拉非尼耐药HCC中干细胞样特性的维持存在因果关系，在很大程度上仍然未知。在这项研究中，我们报告了赖氨酸特异性组蛋白去甲基化酶1A（KDM 1A或LSD 1）的活性是长期索拉非尼治疗后癌症干细胞出现所必需的。因此，KDM 1A抑制剂，如帕吉林和GSK 2879552，显著抑制索拉非尼耐药HCC细胞的干细胞样特性。从机制上讲，KDM 1A抑制剂可抑制Wnt信号通路上游多个负调节因子的表达，从而下调β-连环蛋白通路。更重要的是，KDM 1A抑制使索拉非尼耐药HCC细胞在体内对索拉非尼重新敏感，至少通过减少CSC池来赋予，这表明这种治疗组合有希望的机会。总之，这些发现表明KDM 1A抑制剂可用于减轻索拉非尼的获得性耐药性，从而增加索拉非尼在HCC患者中的治疗效果。(C)2017爱思唯尔B. V.保留所有权利。
Use of the tyrosine kinase inhibitor sorafenib in patients with advanced hepatocellular carcinoma (HCC) is often hindered by the development of resistance, which has been recently shown to be associated with the emergence of a cancer stem cell (CSC) subpopulation. However, it remains largely unknown whether epigenetic mechanisms, especially histone posttranslational modifications, are causally linked to the maintenance of stem-like properties in sorafenib-resistant HCC. In this study, we report that the activity of lysine-specific histone demethylase 1A (KDM1A or LSD1) is required for the emergence of cancer stem cells following prolonged sorafenib treatment. As such, KDM1A inhibitors, such as pargyline and GSK2879552, dramatically suppress stem-like properties of sorafenib-resistant HCC cells. Mechanistically, KDM1A inhibitors derepress the expression of multiple upstream negative regulators of the Wnt signaling pathway to downregulate the beta-catenin pathway. More importantly, KDM1A inhibition resensitizes sorafenib-resistant HCC cells to sorafenib in vivo, at least impart through reducing a CSC pool, suggesting a promising opportunity for this therapeutic combination. Together, these findings suggest that KDM1A inhibitors may be utilized to alleviate acquired resistance to sorafenib, thus increasing the therapeutic efficacy of sorafenib in HCC patients. (C) 2017 Elsevier B.V. All rights reserved.