BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma.

Williams CS, Zhang B, Smith JJ, Jayagopal A, Barrett CW, Pino C, Russ P, Presley SH, Peng D, Rosenblatt DO, Haselton FR, Yang JL, Washington MK, Chen X, Eschrich S, Yeatman TJ, El-Rifai W, Beauchamp RD, Chang MS
J Clin Invest. 2011 121 (10): 4056-69

PMID: 21911938 · PMCID: PMC3195453 · DOI:10.1172/JCI44228

The acquisition of a mesenchymal phenotype is a critical step in the metastatic progression of epithelial carcinomas. Adherens junctions (AJs) are required for suppressing this epithelial-mesenchymal transition (EMT) but less is known about the role of tight junctions (TJs) in this process. Here, we investigated the functions of blood vessel epicardial substance (BVES, also known as POPDC1 and POP1), an integral membrane protein that regulates TJ formation. BVES was found to be underexpressed in all stages of human colorectal carcinoma (CRC) and in adenomatous polyps, indicating its suppression occurs early in transformation. Similarly, the majority of CRC cell lines tested exhibited decreased BVES expression and promoter DNA hypermethylation, a modification associated with transcriptional silencing. Treatment with a DNA-demethylating agent restored BVES expression in CRC cell lines, indicating that methylation represses BVES expression. Reexpression of BVES in CRC cell lines promoted an epithelial phenotype, featuring decreased proliferation, migration, invasion, and anchorage-independent growth; impaired growth of an orthotopic xenograft; and blocked metastasis. Conversely, interfering with BVES function by expressing a dominant-negative mutant in human corneal epithelial cells induced mesenchymal features. These biological outcomes were associated with changes in AJ and TJ composition and related signaling. Therefore, BVES prevents EMT, and its epigenetic silencing may be an important step in promoting EMT programs during colon carcinogenesis.

MeSH Terms (24)

Adenocarcinoma Adherens Junctions Animals Cell Adhesion Molecules Cell Line, Tumor Colonic Neoplasms Colonic Polyps Colorectal Neoplasms DNA Methylation Epithelial-Mesenchymal Transition Epithelium, Corneal Gene Expression Gene Silencing Humans Membrane Proteins Mice Mice, Nude Muscle Proteins Mutation Neoplasm Transplantation Promoter Regions, Genetic Signal Transduction Tight Junctions Transplantation, Heterologous

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