曲古抑菌素 A 通过 BRD4/ERK1/2 依赖性通路促进食管鳞癌细胞迁移和 EMT。
Trichostatin A promotes esophageal squamous cell carcinoma cell migration and EMT through BRD4/ERK1/2-dependent pathway.
机构信息
Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.
Esophageal Cancer Institute of Xinxiang Medical University, Weihui, China.
出版信息
Cancer Med. 2021 Aug;10(15):5235-5245. doi: 10.1002/cam4.4059. Epub 2021 Jun 23.
BACKGROUND
Histone deacetylases (HDACs) have been demonstrated to be aberrantly activated in tumorigenesis and cancer development. Thus, HDAC inhibitors (HDACIs) are considered to be promising anti-cancer therapeutics. However, recent studies have shown that HDACIs promote the migration of many cancer cells. Therefore, there is a need to elucidate the underlying mechanisms of HDACIs on cancer cell migration to establish a combination therapy that overcomes HDACI-induced cell migration.
METHODS
KYSE-150 and EC9706 cells were treated differently. Effects of drugs and siRNA treatment on tumor cell migration and cell signaling pathways were investigated by transwell migration assy. Gene expression for SNAI2 was tested by RT-qPCR. Western blot analysis was employed to detect the level of E-cadherin, β-catenin, vimentin,Slug，ERK1/2, H3, PAI-1 and BRD4. The effect of drugs on cell morphology was evaluated through phase-contrast microscopic images.
RESULTS
TSA promotes epithelial-mesenchymal transition (EMT) in ESCC cells by downregulating the epithelial marker E-cadherin and upregulating mesenchymal markers β-catenin, vimentin, Slug, and PAI-1. Knockdown of Slug by siRNA or inhibition of PAI-1 clearly suppressed TSA-induced ESCC cell migration and resulted in the reversal of TSA-triggered E-cadherin, β-catenin, and vimentin expression. However, no crosstalk between Slug and PAI-1 was observed in TSA-treated ESCC cells. Blocking ERK1/2 activation also inhibited TSA-induced ESCC cell migration, EMT, and upregulation of Slug and PAI-1 levels in ESCC cells. Interestingly, inhibition of BRD4 suppressed TSA-induced ESCC cell migration and attenuated TSA-induced ERK1/2 activation and upregulation of Slug and PAI-1 levels.
CONCLUSIONS
Our data indicate the existence of at least two separable ERK1/2-dependent signaling pathways in TSA-mediated ESCC cell migration: an ERK1/2-Slug branch and an ERK1/2-PAI-1 branch. Both branches of TSA-induced ESCC cell migration appear to favor the EMT process, while BRD4 is responsible for two separable ERK1/2-dependent signaling pathways in TSA-mediated ESCC cell migration.
背景
组蛋白去乙酰化酶（HDACs）已被证明在肿瘤发生和癌症发展中异常激活。因此，HDAC 抑制剂（HDACIs）被认为是有前途的抗癌治疗药物。然而，最近的研究表明，HDACIs 促进了许多癌细胞的迁移。因此，有必要阐明 HDACIs 对癌细胞迁移的潜在机制，以建立一种联合治疗方法来克服 HDACI 诱导的细胞迁移。
方法
用不同的方法处理 KYSE-150 和 EC9706 细胞。通过 Transwell 迁移测定法研究药物和 siRNA 处理对肿瘤细胞迁移和细胞信号通路的影响。通过 RT-qPCR 检测 SNAI2 的基因表达。采用 Western blot 分析检测 E-cadherin、β-catenin、vimentin、Slug、ERK1/2、H3、PAI-1 和 BRD4 的水平。通过相差显微镜图像评估药物对细胞形态的影响。
结果
TSA 通过下调上皮标志物 E-cadherin 和上调间充质标志物 β-catenin、vimentin、Slug 和 PAI-1 促进 ESCC 细胞发生上皮-间充质转化（EMT）。siRNA 敲低 Slug 或抑制 PAI-1 可明显抑制 TSA 诱导的 ESCC 细胞迁移，并导致 TSA 触发的 E-cadherin、β-catenin 和 vimentin 表达逆转。然而，在 TSA 处理的 ESCC 细胞中没有观察到 Slug 和 PAI-1 之间的串扰。阻断 ERK1/2 激活也抑制 TSA 诱导的 ESCC 细胞迁移、EMT 以及 Slug 和 PAI-1 水平的上调。有趣的是，抑制 BRD4 可抑制 TSA 诱导的 ESCC 细胞迁移，并减弱 TSA 诱导的 ERK1/2 激活和 Slug 和 PAI-1 水平的上调。
结论
我们的数据表明，在 TSA 介导的 ESCC 细胞迁移中，至少存在两条可分离的 ERK1/2 依赖性信号通路：ERK1/2-Slug 分支和 ERK1/2-PAI-1 分支。TSA 诱导的 ESCC 细胞迁移的这两个分支似乎都有利于 EMT 过程，而 BRD4 负责 TSA 介导的 ESCC 细胞迁移中两条可分离的 ERK1/2 依赖性信号通路。
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