FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness.
FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness.
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FOXM1 通过调节 UHRF1 控制的癌细胞干性来促进紫杉烷耐药性。
DOI：
10.1038/s41419-018-0631-9
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发表时间：
2018-05-11
影响因子：
9
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Yuan B;Liu Y;Yu X;Yin L;Peng Y;Gao Y;Zhu Q;Cao T;Yang Y;Fan X;Li X
治疗诱导的癌症干细胞（CSC）扩增已被确定为导致治疗耐药性的最关键因素之一，但这种适应的机制尚未完全了解。UHRF 1是一种关键的表观遗传调节因子，负责治疗抗性，并控制干细胞的自我更新。在本研究中，建立了紫杉烷耐药癌细胞并扩增了干细胞样癌细胞。UHRF1在紫杉烷耐药的癌细胞中过表达，保持了CSC的特征。在体外和体内，UHRF 1缺失克服了紫杉烷耐药性。此外，据报道FOXM1在CSC的治疗抗性和自我更新中发挥作用。FOXM1和UHRF1在前列腺癌组织和细胞中高度相关，FOXM1通过以E2F非依赖性方式调节uhrf1基因转录来调节CSC，FOXM1蛋白直接结合于uhrf1基因启动子处的FKH基序。本研究阐明了FOXM1通过UHRF1介导的信号通路控制CSC和紫杉烷耐药的新机制，并验证了FOXM1和UHRF1是克服紫杉烷耐药的两个潜在治疗靶点。
Therapy-induced expansion of cancer stem cells (CSCs) has been identified as one of the most critical factors contributing to therapeutic resistance, but the mechanisms of this adaptation are not fully understood. UHRF1 is a key epigenetic regulator responsible for therapeutic resistance, and controls the self-renewal of stem cells. In the present study, taxane-resistant cancer cells were established and stem-like cancer cells were expanded. UHRF1 was overexpressed in the taxane-resistant cancer cells, which maintained CSC characteristics. UHRF1 depletion overcame taxane resistance in vitro and in vivo. Additionally, FOXM1 has been reported to play a role in therapeutic resistance and the self-renewal of CSCs. FOXM1 and UHRF1 are highly correlated in prostate cancer tissues and cells, FOXM1 regulates CSCs by regulating uhrf1 gene transcription in an E2F-independent manner, and FOXM1 protein directly binds to the FKH motifs at the uhrf1 gene promoter. This present study clarified a novel mechanism by which FOXM1 controls CSCs and taxane resistance through a UHRF1-mediated signaling pathway, and validated FOXM1 and UHRF1 as two potential therapeutic targets to overcome taxane resistance.
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