Forkhead Box Q1 Is a Novel Target of Breast Cancer Stem Cell Inhibition by Diallyl Trisulfide
Forkhead Box Q1 Is a Novel Target of Breast Cancer Stem Cell Inhibition by Diallyl Trisulfide
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DOI：
10.1074/jbc.m116.715219
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发表时间：
2016-06-24
影响因子：
4.8
通讯作者：
Singh, Shivendra V.
中科院分区：
文献类型：
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作者：
Kim, Su-Hyeong;Kaschula, Catherine H.;Singh, Shivendra V.
大蒜的代谢副产物二烯丙基三硫化物(DATS)在体外和体内都能抑制乳腺癌细胞的生长。这项研究表明，DATS以乳腺癌干细胞(BCSC)为靶点。MCF-7和SUM159人乳腺癌细胞暴露于药物浓度DATS(2.5和5M)后，对BCSC的抑制作用呈剂量依赖关系，这一结果可通过大气片试验和流式细胞术分析乙醛脱氢酶1(ALDH1)活性和CD44(高)/CD24(低)/上皮特异性抗原阳性分数来证实。DATS对BCSC的抑制作用与FoxQ1蛋白水平降低有关。在MCF-7和SUM159细胞中过表达FoxQ1可增加ALDH1活性和CD49f(+)/CD24(-)比例。FoxQ1的过表达显著减弱了DATS处理对ALDH1活性和/或乳房膜形成的抑制。与这些结果一致的是，使用小发夹RNA稳定地敲除FoxQ1增强了DATS对BCSC的抑制。肿瘤干细胞相关基因的表达谱表明，FoxQ1可能负向调节Dachshund Homolog 1(DACH1)的表达，DACH1在浸润性乳腺癌中表达缺失。染色质免疫沉淀证实了FoxQ1在DACH1启动子上的招募。此外，DACH1的可诱导表达增强了DATS对BCSC的抑制作用。FoxQ1蛋白在三阴性乳腺癌组织中的表达明显高于正常乳腺组织。此外，在乳腺癌细胞系和肿瘤中，FoxQ1和DACH1基因的表达呈负相关。DATS对移植瘤的体内ALDH1活性有抑制作用。这些结果表明，FoxQ1是DATS抑制BCSC的一个新靶点。
Diallyl trisulfide (DATS), a metabolic byproduct of garlic, is known to inhibit the growth of breast cancer cells in vitro and in vivo. This study demonstrates that DATS targets breast cancer stem cells (bCSC). Exposure of MCF-7 and SUM159 human breast cancer cells to pharmacological concentrations of DATS (2.5 and 5 m) resulted in dose-dependent inhibition of bCSC, as evidenced by a mammosphere assay and flow cytometric analysis of aldehyde dehydrogenase 1 (ALDH1) activity and the CD44(high)/CD24(low)/epithelial specific antigen-positive fraction. DATS-mediated inhibition of bCSC was associated with a decrease in the protein level of FoxQ1. Overexpression of FoxQ1 in MCF-7 and SUM159 cells increased ALDH1 activity and the CD49f(+)/CD24(-) fraction. Inhibition of ALDH1 activity and/or mammosphere formation upon DATS treatment was significantly attenuated by overexpression of FoxQ1. In agreement with these results, stable knockdown of FoxQ1 using small hairpin RNA augmented bCSC inhibition by DATS. Expression profiling for cancer stem cell-related genes suggested that FoxQ1 may negatively regulate the expression of Dachshund homolog 1 (DACH1), whose expression is lost in invasive breast cancer. Chromatin immunoprecipitation confirmed recruitment of FoxQ1 at the DACH1 promoter. Moreover, inducible expression of DACH1 augmented DATS-mediated inhibition of bCSC. Expression of FoxQ1 protein was significantly higher in triple-negative breast cancer cases compared with normal mammary tissues. Moreover, an inverse association was observed between FoxQ1 and DACH1 gene expression in breast cancer cell lines and tumors. DATS administration inhibited ALDH1 activity in vivo in SUM159 xenografts. These results indicate that FoxQ1 is a novel target of bCSC inhibition by DATS.