Aberrant methylation and deacetylation of deleted in liver cancer-1 gene in prostate cancer:: Potential clinical applications
Aberrant methylation and deacetylation of deleted in liver cancer-1 gene in prostate cancer:: Potential clinical applications
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DOI：
10.1158/1078-0432.ccr-05-1906
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发表时间：
2006-03-01
影响因子：
11.5
通讯作者：
Popescu, NC
中科院分区：
文献类型：
--
作者：
Guan, M;Zhou, XL;Popescu, NC
目的：肝癌中缺失的1（DLC-1）基因编码具有肿瘤抑制功能的Rho GTP酶激活蛋白，其位于染色体8 p21 -22，这是前列腺癌中经常缺失的区域。本研究旨在确定DLC-1在前列腺癌中是否失调，并评估DLC-1改变对前列腺癌发生的贡献。实验设计：通过实时PCR，甲基化特异性PCR，结果：27例前列腺癌中有10例（37%）、5例前列腺癌细胞系中有3例（60%）、21例良性前列腺增生中有5例（24%）DCL-1 mRNA表达下调或缺失。DLC-1启动子甲基化在27例前列腺癌中的13例（48%）和2例匹配的正常组织中以及21例良性前列腺增生中的15例（71%）中被鉴定，但在10例非癌个体的正常前列腺组织中不存在。仅在3例前列腺癌和1例良性前列腺增生中发现基因组缺失。DLC-1蛋白在27例前列腺癌和21例良性前列腺增生中分别有8例（30%）和11例（52%）未检出。DLC-1甲基化与前列腺癌患者的年龄相关（P = 0.006），与良性前列腺增生患者的前列腺特异性抗原血液水平相关（P = 0.029）。三种前列腺癌细胞系的处理（PC-3、LNCaP和22 Rv 1）表达低水平的DLC-1转录物，DNA甲基转移酶或组蛋白脱乙酰酶的抑制剂增加DLC-1表达。这些结果表明，DLC的转录沉默-1通过两种表观遗传机制是常见的，可能参与前列腺癌和良性前列腺增生的发病机制，在前列腺癌的早期检测和基因治疗中具有潜在的临床应用价值。
Purpose: The deleted in liver cancer-1 (DLC-1) gene that encodes a Rho GTPase-activating protein with tumor suppressor function is located on chromosome 8p21-22, a region frequently deleted in prostate carcinomas. This study was designed to determine whether DLC-1 is deregulated in prostate carcinomas and to assess the contribution of DLC-1 alterations to prostate carcinogenesis.Experimental Design: Primary prostate carcinomas, prostate carcinoma cell lines, benign prostatic hyperplasias, and normal prostatic tissues were examined for detection of functional and structural alterations of the DLC-1 gene by real-time PCR, methylation-specific PCR, and Southern and Western blots.Results: Down-regulation or loss of DCL-1 mRNA expression was detected in 10 of 27 (37%) prostate carcinomas, 3 of 5 (60%) prostate carcinoma cell lines, and 5 of 21 (24%) benign prostatic hyperplasias. DLC-1 promoter methylation was identified in 13 of 27 (48%) prostate carcinomas and 2 matching normal tissues and in 15 of 21 (71%) benign prostatic hyperplasias but was absent in 10 normal prostatic tissues from noncancerous individuals. Genomic deletions were found in only 3 prostate carcinomas and 1 benign prostatic hyperplasia. DLC-1 protein was not detected in 8 of 27 (30%) prostate carcinomas and 11 of 21 (52%) benign prostatic hyperplasias. Methylation of DLC-1 correlated with age in prostate carcinoma patients (P = 0.006) and with prostate-specific antigen blood levels in benign prostatic hyperplasia patients (P = 0.029). Treatment of the three prostate carcinoma cell lines (PC-3, LNCaP, and 22 Rv1) expressing a low level of DLC-1 transcripts with inhibitors of DNA methyltransferase or histone deacetylase increased DLC-1 expression.Conclusions: These results show that the transcriptional silencing of DLC-1 by two epigenetic mechanisms is common and may be involved in the pathogenesis of prostate carcinomas and benign prostatic hyperplasias and could have potential clinical application in the early detection and gene therapy of prostate cancer.