Increased nucleotide polymorphic changes in the 5'-untranslated region of δ-catenin (CTNND2) gene in prostate cancer

• Published in: Oncogene Vol. 28; no. 4; pp. 555 - 564
• Main Authors: WANG, T, CHEN, Y.-H, HONG, H, ZENG, Y, ZHANG, J, LU, J.-P, JEANSONNE, B, LU, Q
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 29.01.2009
• Subjects: 5' Untranslated Regions - genetics; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Armadillo Domain Proteins - biosynthesis; Armadillo Domain Proteins - genetics; Biological and medical sciences; Catenins - biosynthesis; Catenins - genetics; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; CpG Islands - genetics; Fundamental and applied biological sciences. Psychology; Gene amplification; Gene Expression Regulation, Neoplastic - genetics; Gene mutations; Genetic aspects; Genetic polymorphisms; Gynecology. Andrology. Obstetrics; Health aspects; Humans; Male; Male genital diseases; Medical sciences; Molecular and cellular biology; Nephrology. Urinary tract diseases; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Point Mutation; Polymorphism, Single Nucleotide; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic - genetics; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Risk factors; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; United States; Urinary system disease; 5'-UTR mutation; Prostate disease; Malignant tumor; Carcinogenesis; ingle-strand conformation polymorphism; Gene amplification; Gene; Mutation; Single nucleotide polymorphism; Methylation; Male genital diseases; Prostate cancer; Catenin; Cancer; Conformation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.399

Cancer pathogenesis involves multiple genetic and epigenetic alterations, which result in oncogenic changes in gene expression. delta-Catenin (CTNND2) is overexpressed in cancer, although the mechanisms of its upregulation are highly variable. Here we report that in prostate cancer, the methylation of CpG islands in the delta-catenin promoter was not a primary regulatory event. There was also no delta-catenin gene amplification. However, using the single-strand conformation polymorphism analysis, we observed the increased nucleotide changes in the 5'-untranslated region of delta-catenin gene in human prostate cancer. At least one such change (-9 G>A) is a true somatic point mutation associated with a high Gleason's score, poorly differentiated prostatic adenocarcinoma. Laser capture microdissection coupled with PCR analyses detected the mutation only in cancerous but not in the adjacent benign prostatic tissues. Using chimeric genes encoding the luciferase reporter, we found that this mutation, but not a random mutation or a mutation that disrupts an upstream open reading frame, resulted in a remarkably higher expression and enzyme activity. This mutation did not affect transcriptional efficiency, suggesting that it promotes delta-catenin translation. This is the first report of delta-catenin gene mutation in cancer and supports the notion that multiple mechanisms contribute to its increased expression in carcinogenesis.