title: BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma.
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.
authors.affiliation: Department of Medicine/GI, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. christopher.williams@vanderbilt.edu
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Williams
authors.forename: Baolin
authors.initials: B
authors.lastname: Zhang
authors.forename: J Joshua
authors.initials: JJ
authors.lastname: Smith
authors.forename: Ashwath
authors.initials: A
authors.lastname: Jayagopal
authors.forename: Caitlyn W
authors.initials: CW
authors.lastname: Barrett
authors.forename: Christopher
authors.initials: C
authors.lastname: Pino
authors.forename: Patricia
authors.initials: P
authors.lastname: Russ
authors.forename: Sai H
authors.initials: SH
authors.lastname: Presley
authors.forename: DunFa
authors.initials: D
authors.lastname: Peng
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Rosenblatt
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Haselton
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Yang
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Steven
authors.initials: S
authors.lastname: Eschrich
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Yeatman
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Beauchamp
authors.forename: Min S
authors.initials: MS
authors.lastname: Chang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D022005:Adherens Junctions / Q000473:pathology / Q000502:physiology; D000818:Animals; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003111:Colonic Polyps / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D019175:DNA Methylation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D019573:Epithelium, Corneal / Q000166:cytology* / Q000502:physiology*; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009124:Muscle Proteins; D009154:Mutation; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D019108:Tight Junctions / Q000473:pathology / Q000502:physiology; D014183:Transplantation, Heterologous
chemical_list: D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009124:Muscle Proteins; C530749:POPDC1 protein, human