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Analysis of epigenetic mechanisms of nuclear receptor expression in prostatic carcinogenesis

核受体表达在前列腺癌发生中的表观遗传机制分析

基本信息

批准号：
13670170
负责人：
WATANABE Masatoshi
金额：
$ 1.79万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670170/
关键词：
prostate cancer epigenetics nuclear receptor methylation acetylation

项目摘要

Epigenetic mechanisms including DNA methylation and histone deacetylation are thought to play important roles in gene transcriptional inactivation. We have reported the importance of that epigenetic regulations including CpG methylation and histone acetylation in the regulation of the AR. In addition, these results suggested involvement of methylation in expression of nuclear receptors. The retinoic acid receptor (RAR) β gene is a putative tumor suppressor gene on chromosome 3p24, where a high incidence of loss of heterozygosity is detected in many types of tumors. Selective loss or down-regulation of RARβ mRNA and protein has been reported in prostate cancers (PCas), although the mechanisms remain unclear. We investigated the role of epigenetic modification in RARβ2 gene silencing. Aberrant methylation was detected in 11 of 14 (79%) primary PCas, 9 of 10 (90%) hormone-refractory PCas, and 2 of 4 (50%) PCa cell lines, but not in any normal prostate samples. Chromatin immunoprecipitation assay showed that all RARβ2-negative cells (LNCaP, PC3, and DU145) were hypoacetylated at both histones H3 and H4. After exposure to 5-aza-2'-deoxycytidine treatment, Trichostatin A and all-trans retinoic acid induced partial demethylation, increased accumulation of acetylated histones, and markedly restored the expression of RARβ2 in RARβ2-negative cells. These results suggest that the RARβ2 gene may be one of the frequently silenced genes by epigenetic modifications in PCa. In addition, we found that methylation of the CD44 was related with prostate cancer progression. Our data shows that epigenetic mechanisms may be involved in expression of cancer-related genes.

表观遗传机制，包括DNA甲基化和组蛋白去乙酰化，被认为在基因转录失活中起着重要作用。我们已经报道了包括CpG甲基化和组蛋白乙酰化在内的表观遗传调控在AR调控中的重要性。此外，这些结果表明甲基化参与了核受体的表达。维甲酸受体β基因是位于染色体3p24上的一种可能的肿瘤抑制基因，在许多类型的肿瘤中都有很高的杂合性丢失。已有报道在前列腺癌(PCAS)中选择性缺失或下调β基因和蛋白，尽管其机制尚不清楚。我们研究了表观遗传修饰在RARβ2基因沉默中的作用。在14个原发PCAS中有11个(79%)、10个激素不敏感PCAS中有9个(90%)和4个Pca细胞系中有2个(50%)检测到异常甲基化，但在任何正常前列腺标本中均未检测到甲基化。染色质免疫沉淀分析显示，所有RARβ2阴性细胞(LNCaP、PC3和DU145)在组蛋白H3和H4上均发生低乙酰化。经5-氮-2‘-脱氧胞苷处理后，曲古菌素A和全反式维甲酸可诱导RARβ2阴性细胞部分去甲基化，增加乙酰化组蛋白的积聚，并显著恢复RARβ2的表达。这些结果表明，RARβ2基因可能是PCa中经常被表观遗传修饰而沉默的基因之一。此外，我们还发现CD44的甲基化与前列腺癌的进展有关。我们的数据显示，表观遗传机制可能涉及癌症相关基因的表达。