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

doi:10.1158/0008-5472.CAN-04-3398

EMT and Cancer Progression and Treatment

Molecular Biology, Pathobiology, and Genetics

Functional Loss of the ${gamma}$ -Catenin Gene through Epigenetic and Genetic Pathways in Human Prostate Cancer

Hiroaki Shiina², Julia E. Breault¹, William W. Basset¹, Hideki Enokida¹, Shinji Urakami¹, Long-Cheng Li¹, Steven T. Okino¹, Masao Deguchi¹, Masanori Kaneuchi¹, Masaharu Terashima³, Tatsuaki Yoneda², Kazushi Shigeno², Peter R. Carroll¹, Mikio Igawa² and Rajvir Dahiya¹

¹ Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California and Departments of ² Urology and ³ Biochemistry and Molecular Medicine, Shimane University School of Medicine, Izumo, Japan

Requests for reprints: Rajvir Dahiya, Urology Research Center (112F), University of California San Francisco and Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121. Phone: 415-750-6964; Fax: 415-750-6639; E-mail: rdahiya{at}urol.ucsf.edu.

${gamma}$ -Catenin is a cell adhesion molecule and a candidate mediatorof Wnt signal transduction. We hypothesized that impaired regulationof ${gamma}$ -catenin through genetic and epigenetic pathways is associatedwith 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 analyzedin cultured prostate cancer cell lines, 180 localized prostatecancers, 69 benign prostatic hyperplasias, and 11 hormone refractoryprostate cancers (HRPC). In prostate cancer cell lines (DuPro,LNCaP, ND-1, and PC3), ${gamma}$ -catenin mRNA transcripts were increasedafter 5-aza-2'-deoxycytidine treatment. In localized prostatecancer, ${gamma}$ -catenin expression was lower but prevalence of ${gamma}$ -cateninmethylation was higher compared with benign prostatic hyperplasia.However, ${gamma}$ -catenin methylation did not correlate with Gleasonsum, pT category, or capsular penetration. Among localized prostatecancers with positive ${gamma}$ -catenin methylation, the presence ofLOH at chromosome 17q21 was closely related to down-regulationof ${gamma}$ -catenin mRNA expression. The ${gamma}$ -catenin mutations were notfound in localized prostate cancers, whereas six mutations werefound in five HRPCs within or close to the GSK-3ßconsensus motif phosphorylation site, among which four HRPCsshowed strong nuclear ${gamma}$ -catenin accumulation. In these four HRPCs,Bcl-2 expression was increased, whereas the target of the Wntsignal, c-myc, was only expressed in one HRPC. Therefore, althoughepigenetic ${gamma}$ -catenin methylation is an early event in the developmentof prostate cancer, simultaneous events of epigenetic cytosine-phosphate-guaninemethylation and genetic LOH may be responsible for functionalloss of ${gamma}$ -catenin. The ${gamma}$ -catenin mutation related to Bcl-2 overexpressionhas a significant effect on the pathogenesis of HRPC. This isthe first report to characterize the epigenetic and geneticregulation of ${gamma}$ -catenin in human prostate cancer.

Key Words: ${gamma}$ -catenin • methylation • human prostate cancer • mutation • LOH and apoptosis

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