A critical role of histone deacetylases, Mbd3/NuRD and Tet2 in epithelial-mesenchymal cell plasticity and in tumor invasion and metastasis

We have generated and employed reversible and irreversible EMT models of murine breast cancer cells to identify the key players establishing cell state transitions during a reversible and an irreversible EMT. We demonstrate that the Mbd3/NuRD complex, involving histone deacetylases (HDACs) and Tet2 hydroxylase, acts as an epigenetic block in epithelial-mesenchymal plasticity. These epigenetic modifiers keep breast cancer cells in a stable mesenchymal state, and their pharmacological inhibition or genetic ablation leads to a mesenchymal-epithelial transition (MET) and represses primary tumor growth and metastasis formation of highly aggressive, mesenchymal breast cancer cells. We performed RNA-sequencing of 2 replicates of each treatment and cell line

本研究构建并应用了小鼠乳腺癌细胞的可逆与不可逆上皮间质转化（epithelial-mesenchymal transition, EMT）模型，以鉴定介导可逆及不可逆EMT过程中细胞状态转换的关键调控因子。研究证实，包含组蛋白去乙酰化酶（HDACs）与Tet2羟化酶的Mbd3/NuRD复合物，可作为上皮间质可塑性（epithelial-mesenchymal plasticity, EMP）的表观遗传阻断因子。这类表观遗传修饰因子可将乳腺癌细胞维持于稳定的间充质状态；对其进行药物抑制或基因敲除，可诱导间质上皮转化（mesenchymal-epithelial transition, MET），并抑制高侵袭性间充质乳腺癌细胞的原发肿瘤生长与转移形成。本研究对每种处理条件及细胞系的2个生物学重复样本开展了RNA测序（RNA-seq）。