title: Epigenetic silencing of claudin-6 promotes anchorage-independent growth of breast carcinoma cells.
abstract: Cancer cells often exhibit loss of functional tight junctions (TJ), and disruption of the TJ structure is associated with cancer development. However, whether loss of a certain type of claudin, an integral membrane protein of TJ, is involved in malignant phenotypes remains to be clarified. Based on a report that claudin-6 functions as a tumor suppressor for breast cancer, the authors show here that suppression of claudin-6 expression results in increased resistance to various apoptogens, and causally enhances anchorage-independent growth properties. Because claudin-6 expression is partially silenced by promoter CpG island hypermethylation in MCF7 breast carcinoma cells, a synergistic effect of a demethylator and histone deacetylase inhibitor up-regulates the expression of endogenous claudin-6, which is sufficient for apoptotic sensitization and abrogation of colony-forming efficacy. In addition, decreased expression of claudin-6 promotes cellular invasiveness and transendothelial migration, accompanied by an increase in matrix metalloproteinase activity. These data suggest that the methylator phenotype of claudin-6 may at least partially contribute to enhanced tumorigenic and invasive properties of breast carcinoma cells.
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan. osanaim@sapmed.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Osanai
authors.forename: Masaki
authors.initials: M
authors.lastname: Murata
authors.forename: Hideki
authors.initials: H
authors.lastname: Chiba
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.forename: Norimasa
authors.initials: N
authors.lastname: Sawada
mesh_terms: D023102:Anoikis / Q000502:physiology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D057167:Claudins; D003114:Colony-Forming Units Assay; D018899:CpG Islands; D019175:DNA Methylation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019108:Tight Junctions; D014407:Tumor Cells, Cultured
chemical_list: D057167:Claudins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C122101:claudin 6