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

Christopher S. Williams, Baolin Zhang, J. Joshua Smith, Ashwath Jayagopal, Caitlyn W. Barrett, Christopher Pino, Patricia Russ, Sai H. Presley, Dun Fa Peng, Daniel O. Rosenblatt, Frederick R. Haselton, Jin Long Yang, M. Kay Washington, Xi Chen, Steven Eschrich, Timothy J. Yeatman, Wael El-Rifai, R. Daniel Beauchamp, Min S. Chang

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4056-4069
Number of pages14
JournalJournal of Clinical Investigation
Volume121
Issue number10
DOIs
StatePublished - Oct 3 2011
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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