Transcriptional repression of epithelial cell adhesion molecule contributes to p53 control of breast cancer invasion.
p53 is a tumor suppressor gene with well-characterized roles in cell cycle regulation, apoptosis, and maintenance of genome stability. Recent evidence suggests that p53 may also contribute to the regulation of migration and invasion. Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that is overexpressed in the majority of human epithelial carcinomas, including breast and colorectal carcinomas. We show by chromatin immunoprecipitation assays that p53 interacts with a candidate p53 binding site within the EpCAM gene. p53-mediated transcriptional repression of EpCAM was confirmed in gain-of-function and loss-of-function experimental systems. Induction of wild-type p53 was associated with a significant dose-dependent decrease in EpCAM expression; conversely, specific ablation of p53 was associated with a significant increase in EpCAM expression. At the functional level, specific ablation of p53 expression is associated with increased breast cancer invasion, and this effect is abrogated by concomitant specific ablation of EpCAM expression. Taken together, these biochemical and functional data are the first demonstration that (a) wild-type p53 protein binds to a response element within the EpCAM gene and negatively regulates EpCAM expression, and (b) transcriptional repression of EpCAM contributes to p53 control of breast cancer invasion.
Sankpal
Narendra V
NV
Section of Endocrine and Oncologic Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Willman
Michael W
MW
Fleming
Timothy P
TP
Mayfield
John D
JD
Gillanders
William E
WE
D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000071858:Epithelial Cell Adhesion Molecule; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D011487:Protein Conformation; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53