Methylation of the androgen receptor minimal promoter silences transcription in human prostate cancer.
Methylation of the androgen receptor minimal promoter silences transcription in human prostate cancer.
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发表时间：
2000-07
期刊：
影响因子：
11.2
通讯作者：
Hidefumi Kinoshita;Yan Shi;C. Sandefur;Lorraine F. Meisner;Chawnshang Chang;A. Choon;C. Reznikoff-C.-Rezniko
中科院分区：
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作者：
Hidefumi Kinoshita;Yan Shi;C. Sandefur;Lorraine F. Meisner;Chawnshang Chang;A. Choon;C. Reznikoff-C.-Rezniko
晚期非依赖性前列腺癌的特征在于20-30%的肿瘤中雄激素受体（AR）表达的显著丧失。这种现象背后的转录阻断机制尚不清楚，但我们提出AR启动子中CpG位点的甲基化可能可逆地抑制AR的转录（D. F. Jarrard等人，Cancer Res.，58：5310-5314，1998）。在这项研究中，使用亚硫酸氢盐测序对一系列AR表达阳性和阴性的前列腺癌细胞进行了详细的甲基化分析。我们发现，AR启动子中几个共有序列（从-131到-121和+44到+54）的甲基化与转移性非依赖性前列腺癌细胞系中AR表达的丧失密切相关。这些甲基化的共有位点与对AR转录至关重要的最小启动子区域相关。在人类组织中，在表达AR的正常或原发性前列腺癌中没有甲基化。从死于非肿瘤依赖性前列腺癌的男性中获得的15个肿瘤中有4个显示出AR表达的显著丧失，并且这些AR阴性肿瘤中有2个（50%）含有AR甲基化。我们的结论是AR启动子含有特定的CpG甲基化热点，是基因沉默的标志。此外，AR甲基化可能代表在AR表达丢失的晚期前列腺癌亚组中激素依赖性发展中重要的表型。AR甲基化的发现也代表了第一份与体细胞男性癌症相关的X连锁基因异常甲基化的报告。
Advanced hormone-independent prostate cancer is characterized by a significant loss of androgen receptor (AR) expression in 20-30% of the tumors. The transcriptional block underlying this phenomenon is not known, but we have proposed that methylation of CpG sites in the AR promoter may reversibly inactivate transcription of the AR (D. F. Jarrard et al, Cancer Res., 58: 5310-5314, 1998). In this study, detailed methylation analysis using bisulfite sequencing was performed on a series of AR expression-positive and -negative prostate cancer cells. We found that methylation of several consensus sequences in the AR promoter (from -131 to -121 and +44 to +54) are tightly linked to the loss of AR expression in metastatic hormone-independent prostate cancer cell lines. These consensus sites of methylation correlate with the minimal promoter region critical for AR transcription. In human tissues, no methylation was demonstrated in normal or primary prostate cancers that express the AR. Four of 15 tumors obtained from men who had died from hormone-independent prostate cancer demonstrated a significant loss of AR expression immunohistochemically and two (50%) of these AR-negative tumors contained AR methylation. We conclude that the AR promoter contains specific CpG methylation hot spots that are markers for gene silencing. Furthermore, AR methylation may represent a phenotype important in the development of hormone independence in a subset of advanced prostate cancer in which AR expression is lost. The finding of AR methylation also represents the first report of aberrant methylation on an X-linked gene associated with a somatic male cancer.