title: DNA methylation analyses of the connexin gene family reveal silencing of GJC1 (Connexin45) by promoter hypermethylation in colorectal cancer.
abstract: Gap junctions are specialized plasma membrane domains consisting of channels formed by members of the connexin protein family. Gap junctional intercellular communication is often lost in cancers due to aberrant localization or downregulation of connexins, and connexins are therefore suggested to act as tumor suppressor genes in various tissues. The aim of this study was to investigate the expression pattern and DNA promoter methylation status of connexins in colorectal cancer. Expression of six (GJA1, GJA9, GJB1, GJB2, GJC1 and GJD3) connexin genes was detected in normal colonic tissue samples. GJC1 expression was reduced in colorectal carcinomas compared to normal tissue samples. All analyzed connexins were hypermethylated in colon cancer cell lines, although at various frequencies. GJA4, GJB6 and GJD2 were hypermethylated in 60% (29/48), 25% (12/48) and 96% (46/48) of primary colorectal carcinomas, respectively. However, the methylation status was not associated with gene expression. GJC1 has two alternative promoters, which were methylated in 42% (32/76) and 38% (25/65) of colorectal tumors, and in none of the normal mucosa samples. Expression of GJC1 was significantly lower in methylated compared with unmethylated samples (p < 0.01) and was restored in cell lines treated with the demethylating drug 5-aza-2'deoxycytidine. Taken together, DNA hypermethylation of the promoter region of GJC1, encoding connexin45, is an important mechanism in silencing gene expression in colorectal cancer.
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Radiumhospitalet - Oslo University Hospital, Oslo, Norway.
authors.forename: Solveig
authors.initials: S
authors.lastname: Sirnes
authors.forename: Hilde
authors.initials: H
authors.lastname: Honne
authors.forename: Deeqa
authors.initials: D
authors.lastname: Ahmed
authors.forename: Stine Aske
authors.initials: SA
authors.lastname: Danielsen
authors.forename: Torleiv O
authors.initials: TO
authors.lastname: Rognum
authors.forename: Gunn Iren
authors.initials: GI
authors.lastname: Meling
authors.forename: Edward
authors.initials: E
authors.lastname: Leithe
authors.forename: Edgar
authors.initials: E
authors.lastname: Rivedal
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Guro E
authors.initials: GE
authors.lastname: Lind
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002450:Cell Communication / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D017629:Gap Junctions / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; C082920:connexin 45; D000072259:Connexin 26