YC-1 inhibits proliferation of breast cancer cells by down-regulating EZH2 expression via activation of c-Cbl and ERK
YC-1 inhibits proliferation of breast cancer cells by down-regulating EZH2 expression via activation of c-Cbl and ERK
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DOI：
10.1111/bph.12708
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发表时间：
2014-09-01
影响因子：
7.3
通讯作者：
Kuo, Sheng-Chu
中科院分区：
文献类型：
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作者：
Chang, Ling-Chu;Lin, Hui-Yi;Kuo, Sheng-Chu
背景与目的yc -1在许多癌细胞系中表现出强大的抗癌活性。因此，我们在MDA-MB-468异种移植瘤模型中研究了YC-1的体内抗肿瘤效果，并阐明了YC-1在乳腺癌细胞中下调zeste同源增强子2 （EZH2）的机制。实验方法在yc -1处理的乳腺癌细胞和yc -1处理的MDA-MB-468肿瘤标本中，用Western blotting分析EZH2的表达。使用药物抑制剂和短发夹rna介导的敲低来鉴定YC-1下调EZH2的可能信号通路。关键结果syc -1降低MDA-MB-468异种移植物中乳腺癌细胞的活力和肿瘤生长。在乳腺癌细胞中，YC-1以浓度和时间依赖的方式下调EZH2的表达。EZH2的缺失降低了乳腺癌细胞对yc -1诱导的凋亡的增殖和易感性。yc -1处理的MDA-MB-468异种移植小鼠肿瘤标本中EZH2表达被抑制。YC-1增强了EZH2的降解速率和泛素化。YC-1下调EZH2与激活PKA和src - raf - erk介导的信号通路有关。此外，Casitas b系淋巴瘤（c-Cbl）的E3泛素连接酶的缺失可以消除yc -1诱导的细胞凋亡和EZH2的抑制。YC-1快速激活c-Cbl诱导与ERK和EZH2相关的信号传导。结论与意义YC-1通过激活c-Cbl和ERK下调EZH2，诱导乳腺癌细胞凋亡，抑制肿瘤生长。这些数据表明，YC-1是治疗三阴性乳腺癌的潜在候选抗癌药物。
BACKGROUND AND PURPOSEYC-1 exhibits potent anticancer activity via numerous actions in many cancer cell lines. Hence, we investigated the in vivo antitumour efficacy of YC-1 in an MDA-MB-468 xenograft model and elucidated the mechanism of down-regulation of enhancer of zeste homology 2 (EZH2) by YC-1 in breast cancer cells.EXPERIMENTAL APPROACHIn YC-1-treated breast cancer cells and tumour specimens from YC-1-treated MDA-MB-468 xenografts, EZH2 expression was analysed by Western blotting. Pharmacological inhibitors and short hairpin RNA-mediated knockdown were applied to identify possible signalling pathways involved in EZH2 down-regulation by YC-1.KEY RESULTSYC-1 reduced the viability of breast cancer cells and tumour growth in MDA-MB-468 xenografts. In breast cancer cells, YC-1 down-regulated EZH2 expression in a concentration-and time-dependent manner. Depletion of EZH2 reduced the proliferation and susceptibility of breast cancer cells to YC-1-induced apoptosis. EZH2 expression was suppressed in tumour specimens from YC-1-treated MDA-MB-468 xenograft mice. YC-1 enhanced both the degradation rate and ubiquitination of EZH2. The down-regulation of EZH2 by YC-1 was associated with activation of PKA and Src-Raf-ERK-mediated signalling pathways. Furthermore, depletion of Casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase, abolished YC-1-induced apoptosis and suppression of EZH2. YC-1 rapidly activated c-Cbl to induce signalling associated with ERK and EZH2.CONCLUSION AND IMPLICATIONSWe discovered that YC-1 induces apoptosis and inhibits tumour growth of breast cancer cells via down-regulation of EZH2 by activating c-Cbl and ERK. These data suggest that YC-1 is a potential anticancer drug candidate for triple-negative breast cancer.