Functional Loss of the γ-Catenin Gene through Epigenetic and Genetic Pathways in Human Prostate Cancer

Abstract

Abstract;-Catenin is a cell adhesion molecule and a candidate mediator of Wnt signal transduction. We hypothesized that impaired regulation of ;-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 g g-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), g g-catenin mRNA transcripts were increased after 5-aza-2V-deoxycytidine treatment. In localized prostate cancer, ;-catenin expression was lower but prevalence of g g-catenin methylation was higher compared with benign prostatic hyperplasia. However, g g-catenin methylation did not correlate with Gleason sum, pT category, or capsular penetration. Among localized prostate cancers with positive g g-catenin methylation, the presence of LOH at chromosome 17q21 was closely related to down-regulation of g g-catenin mRNA expression. The g g-catenin mutations were not found in localized prostate cancers, whereas six mutations were found in five HRPCs within or close to the GSK-3B consensus motif phosphorylation site, among which four HRPCs showed strong nuclear ;-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 g g-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 ;-catenin. The g g-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 ;-catenin in human prostate cancer. (Cancer Res 2005; 65(6): 2130-8)

Plakoglobin-dependent regulation of keratinocyte APOPTOSIS by Rnd3

“…This would be consistent with data implicating plakoglobin in the development of squamous cell carcinoma through induction of Bcl-2 (Hakimelahi et al, 2000). Nuclear accumulation of plakoglobin and an increase in Bcl-2 expression has also been observed in advanced prostate cancer (Shiina et al, 2005). However, other evidence suggests that plakoglobin functions as a tumour suppressor with loss of heterozygosity being linked to poor clinical outcomes in breast, ovarian and small cell lung cancers (Aberle et al, 1995;Winn et al, 2002).…”

Desmosomes: a role in cancer?

“…Another suggestion is that plakoglobin causes unregulated growth and foci formation (in human squamous carcinoma cells), as a result of induction of the pro-survival gene Bcl-2 and inhibition of apoptosis (Hakimelahi et al, 2000). In support of the latter idea, mutations within or near to a glycogen synthase kinase-3b consensus phosphorylation site have been discovered in advanced hormone refractory prostate cancer, and these coincide with strong nuclear accumulation of plakoglobin and a concomitant increase in Bcl-2 (Shiina et al, 2005). By contrast, in early prostate cancer, it appears to be loss of expression of plakoglobin, as a result of loss of heterozygosity (LOH) and hypermethylation of the plakoglobin promoter, that is important (Shiina et al, 2005).…”

DNA methylation of the RIZ1 gene is associated with nuclear accumulation of p53 in prostate cancer

“…Prior studies have shown that DNA hypermethylation is a crucial mechanism in transcriptional silencing of tumor-related genes in PCa. (6,7) The retinoblastoma protein-interacting zinc finger gene, RIZ1, was isolated with a functional screen for retinoblastoma (Rb)-binding proteins.(8) Domain analysis suggested that RIZ1 is a histone methyltransferase (HMT) specific for the lysine 9 residue of histone H3, an activity known to be linked with transcriptional repression.(9) RIZ1 is considered to be a tumor suppressor gene because it can induce G 2 -M arrest and apoptosis of several types of cancer cells.(10,11) RIZ1 plays an important role in human cancers, as evidenced by genetic mutations. (12)(13)(14) The RIZ1 gene is located on human chromosome 1p36, a region deleted in many human cancers, (15) and chromosome 1p36 is a potential hereditary PCa susceptibility locus.…”

“…Prior studies have shown that DNA hypermethylation is a crucial mechanism in transcriptional silencing of tumor-related genes in PCa. (6,7) The retinoblastoma protein-interacting zinc finger gene, RIZ1, was isolated with a functional screen for retinoblastoma (Rb)-binding proteins.…”

“…Prior studies have shown that DNA hypermethylation is a crucial mechanism in transcriptional silencing of tumor-related genes in PCa. (6,7) The retinoblastoma protein-interacting zinc finger gene, RIZ1, was isolated with a functional screen for retinoblastoma (Rb)-binding proteins. (8) Domain analysis suggested that RIZ1 is a histone methyltransferase (HMT) specific for the lysine 9 residue of histone H3, an activity known to be linked with transcriptional repression.…”