title: Functional Loss of the gamma-catenin gene through epigenetic and genetic pathways in human prostate cancer.
abstract: Gamma-catenin is a cell adhesion molecule and a candidate mediator of Wnt signal transduction. We hypothesized that impaired regulation of gamma-catenin through genetic and epigenetic pathways is associated with the pathogenesis of prostate cancer. To test this hypothesis, cytosine-phosphate-guanine methylation, loss of heterozygosity (LOH), and mutation status of the gamma-catenin gene were analyzed in cultured prostate cancer cell lines, 180 localized prostate cancers, 69 benign prostatic hyperplasias, and 11 hormone refractory prostate cancers (HRPC). In prostate cancer cell lines (DuPro, LNCaP, ND-1, and PC3), gamma-catenin mRNA transcripts were increased after 5-aza-2'-deoxycytidine treatment. In localized prostate cancer, gamma-catenin expression was lower but prevalence of gamma-catenin methylation was higher compared with benign prostatic hyperplasia. However, gamma-catenin methylation did not correlate with Gleason sum, pT category, or capsular penetration. Among localized prostate cancers with positive gamma-catenin methylation, the presence of LOH at chromosome 17q21 was closely related to down-regulation of gamma-catenin mRNA expression. The gamma-catenin mutations were not found in localized prostate cancers, whereas six mutations were found in five HRPCs within or close to the GSK-3beta consensus motif phosphorylation site, among which four HRPCs showed strong nuclear gamma-catenin accumulation. In these four HRPCs, Bcl-2 expression was increased, whereas the target of the Wnt signal, c-myc, was only expressed in one HRPC. Therefore, although epigenetic gamma-catenin methylation is an early event in the development of prostate cancer, simultaneous events of epigenetic cytosine-phosphate-guanine methylation and genetic LOH may be responsible for functional loss of gamma-catenin. The gamma-catenin mutation related to Bcl-2 overexpression has a significant effect on the pathogenesis of HRPC. This is the first report to characterize the epigenetic and genetic regulation of gamma-catenin in human prostate cancer.
authors.affiliation: Department of Urology, Shimane University School of Medicine, Izumo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiina
authors.forename: Julia E
authors.initials: JE
authors.lastname: Breault
authors.forename: William W
authors.initials: WW
authors.lastname: Basset
authors.forename: Hideki
authors.initials: H
authors.lastname: Enokida
authors.forename: Shinji
authors.initials: S
authors.lastname: Urakami
authors.forename: Long-Cheng
authors.initials: LC
authors.lastname: Li
authors.forename: Steven T
authors.initials: ST
authors.lastname: Okino
authors.forename: Masao
authors.initials: M
authors.lastname: Deguchi
authors.forename: Masanori
authors.initials: M
authors.lastname: Kaneuchi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Terashima
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Yoneda
authors.forename: Kazushi
authors.initials: K
authors.lastname: Shigeno
authors.forename: Peter R
authors.initials: PR
authors.lastname: Carroll
authors.forename: Mikio
authors.initials: M
authors.lastname: Igawa
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D019175:DNA Methylation; D051180:Desmoplakins; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011470:Prostatic Hyperplasia / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051185:gamma Catenin
chemical_list: D003598:Cytoskeletal Proteins; D051180:Desmoplakins; C495292:JUP protein, human; D012333:RNA, Messenger; D051185:gamma Catenin