title: EpCAM regulates cell cycle progression via control of cyclin D1 expression.
abstract: The epithelial cell adhesion molecule (EpCAM) is an integral transmembrane protein that is frequently overexpressed in embryonic stem cells, tissue progenitors, carcinomas and cancer-initiating cells. In cancer cells, expression of EpCAM is associated with enhanced proliferation and upregulation of target genes including c-myc. However, the exact molecular mechanisms underlying the observed EpCAM-dependent cell proliferation remained unexplored. Here, we show that EpCAM directly affects cell cycle progression via its capacity to regulate the expression of cyclin D1 at the transcriptional level and depending on the direct interaction partner FHL2 (four-and-a-half LIM domains protein 2). As a result, downstream events such as phosphorylation of the retinoblastoma protein (Rb) and expression of cyclins E and A are similarly affected. In vivo, EpCAM expression strength and pattern are both positively correlated with the proliferation marker Ki67, high expression and nuclear localisation of cyclin D1, and Rb phosphorylation. Thus, EpCAM enhances cell cycle progression via the classical cyclin-regulated pathway.
authors.affiliation: Clinical Cooperation Group Molecular Oncology, Helmholtz-Zentrum München, German Research Center for Environmental Health, and Head and Neck Research Department, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Chaves-Pérez
authors.forename: B
authors.initials: B
authors.lastname: Mack
authors.forename: D
authors.initials: D
authors.lastname: Maetzel
authors.forename: H
authors.initials: H
authors.lastname: Kremling
authors.forename: C
authors.initials: C
authors.lastname: Eggert
authors.forename: U
authors.initials: U
authors.lastname: Harréus
authors.forename: O
authors.initials: O
authors.lastname: Gires
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism; D000071858:Epithelial Cell Adhesion Molecule; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D019925:Cyclin A; D019927:Cyclin E; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D019938:Cyclin D1