EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition.
EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition.
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DOI：
10.1158/0008-5472.can-16-0752
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发表时间：
2016-11-01
期刊：
影响因子：
11.2
通讯作者：
Huang TH
中科院分区：
文献类型：
--
作者：
Hsu YT;Osmulski P;Wang Y;Huang YW;Liu L;Ruan J;Jin VX;Kirma NB;Gaczynska ME;Huang TH
上皮细胞粘附分子（EpCAM）的过度表达与晚期子宫内膜癌有关，但其在这一进展中的作用仍有待阐明。除了其在调节细胞表面粘附的结构作用，在这里，我们证明，EpCAM是一种调节分子，其内化到细胞核打开一个转录程序。EGF/EGFR信号转导的激活触发EpCAM的细胞表面切割，导致其胞质结构域EpICD的核内化。ChIP-seq分析鉴定了由EpICD及其转录伴侣LEF-1共调控的靶基因。网络富集分析进一步揭示了一组105个编码紧密连接、粘附和细胞迁移功能的基因。此外，通过原子力显微镜（AFM）的纳米力学分析显示，EGF刺激的癌细胞的柔软度增加，并且弹性降低，这暗示了上皮-间充质转化（EMT）表型的获得。因此，EpCAM的基因组编辑可能与改变这些纳米机械特性朝向侵袭性较低的表型相关。使用这种综合基因组-生物物理方法，我们首次证明了EpCAM调节的转录与促进晚期子宫内膜癌EMT的细胞生物物理特性改变之间的复杂关系。
Overexpression of epithelial cell adhesion molecule (EpCAM) has been implicated in advanced endometrial cancer, but its roles in this progression remain to be elucidated. In addition to its structural role in modulating cell-surface adhesion, here we demonstrate that EpCAM is a regulatory molecule in which its internalization into the nucleus turns on a transcription program. Activation of EGF/EGFR signal transduction triggered cell-surface cleavage of EpCAM, leading to nuclear internalization of its cytoplasmic domain EpICD. ChIP-seq analysis identified target genes that are co-regulated by EpICD and its transcription partner, LEF-1. Network enrichment analysis further uncovered a group of 105 genes encoding functions for tight junction, adherent and cell migration. Furthermore, nanomechanical analysis by atomic force microscope (AFM) revealed increased softness and decreased adhesiveness of EGF-stimulated cancer cells, implicating acquisition of an epithelial-mesenchymal transition (EMT) phenotype. Thus, genome editing of EpCAM could be associated with altering these nanomechanical properties towards a less aggressive phenotype. Using this integrative genomic-biophysical approach, we demonstrate for the first time an intricate relationship between EpCAM-regulated transcription and altered biophysical properties of cells that promote EMT in advanced endometrial cancer.