title: EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition.
abstract: 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 coregulated 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 microscopy 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. Cancer Res; 76(21); 6171-82. ©2016 AACR.
authors: Departments of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors: Ya-Ting
authors: YT
authors: Hsu
authors: Departments of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors: Pawel
authors: P
authors: Osmulski
authors: Departments of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors: Yao
authors: Y
authors: Wang
authors: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Yi-Wen
authors: YW
authors: Huang
authors: Department of Computer Science, University of Texas at San Antonio, San Antonio, Texas.
authors: Lu
authors: L
authors: Liu
authors: Department of Computer Science, University of Texas at San Antonio, San Antonio, Texas.
authors: Jianhua
authors: J
authors: Ruan
authors: Departments of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors: Victor X
authors: VX
authors: Jin
authors: Departments of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors: Nameer B
authors: NB
authors: Kirma
authors: Departments of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas. huangt3@uthscsa.edu gaczynska@uthscsa.edu.
authors: Maria E
authors: ME
authors: Gaczynska
authors: Departments of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas. huangt3@uthscsa.edu gaczynska@uthscsa.edu.
authors: Tim Hui-Ming
authors: TH
authors: Huang
mesh_terms: D001696:Biomechanical Phenomena; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D000071858:Epithelial Cell Adhesion Molecule / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D000072669:Gene Editing; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000502:physiology; D018625:Microscopy, Atomic Force; D019108:Tight Junctions / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D000071858:Epithelial Cell Adhesion Molecule; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D004815:Epidermal Growth Factor