GSTP1 gene repression in prostate cancer

前列腺癌中的 GSTP1 基因抑制

• 批准号: 6692795
• 负责人: RAKESH SINGAL
• 金额: $ 11.36万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6692795
• 关键词: DNA methylation; JUN kinase; amidohydrolases; binding proteins; carcinogenesis; cell line; cell proliferation; enzyme inhibitors; gene expression; gene induction /repression; genetic promoter element; genetic transcription; glutathione transferase; immunoprecipitation; neoplasm /cancer genetics; neoplastic growth; polymerase chain reaction; prostate neoplasms; transfection

DESCRIPTION (provided by applicant): Glutathione S-transferases (GSTs) are a group of isoenzymes that catalyze intracellular detoxification reactions by conjugating glutathione with electrophilic compounds including carcinogens and exogenous drugs. Among the isoenzymes, the role of the pi class GSTP (GSTP1) in cancer has been studied extensively. Cytosine methylation in GSTP1 regulatory sequences associated with the loss of GSTP1 expression has been observed in a majority of human prostate carcinomas and prostatic intraepithelial neoplasia (PIN). In normal prostate tissue, in contrast, the CpG island of the GSTP1 gene is not methylated and the gene is expressed. We have recently shown that cytosine methylation can repress the GSTP1 gene expression in LNCaP prostate cancer cells and that this effect is possibly mediated by a Methyl Cytosine-binding Protein complex 1(MeCP1) -like complex. We will elucidate further the mechanism of methylation-mediated GSTP1 gene repression by determining the in vivo binding of methyl CpG binding proteins and histone deacetylases with the GSTP1 gene promoter sequences. Since GSTP1 methylation is an early event in prostate carcinogenesis, it has been proposed that rare prostate cells with hypermethylated GSTP1 promoter sequences may undergo clonal expansion because of carcinogen exposure. GSTP1 is an inhibitor of Jun N-terminal kinase (JNK) activity and pharmacologic or genetic manipulation of GSTP1 influences cell proliferation pathways. At present, it is not known if loss of GSTP1 expression promotes the proliferation and/or tumorigenicity of prostate cancer cells. We will determine if proliferation or tumorigenicity of a human prostate cancer cell line, LNCaP, changes with expression of the GSTP1 gene. We would expect that the results obtained from the studies will be relevant to the development of safe and effective pharmacologic and gene-targeting therapies for patients with human prostate cancer, and will further our understanding of DNA methylation and cancer-associated gene silencing.

描述（由申请人提供）： 谷胱甘肽 S-转移酶 (GST) 是一组通过以下方式催化细胞内解毒反应的同工酶： 将谷胱甘肽与亲电化合物（包括致癌物和 外源性药物。在同工酶中，pi 类 GSTP (GSTP1) 在 癌症已被广泛研究。 GSTP1 调控中的胞嘧啶甲基化 与 GSTP1 表达缺失相关的序列已在 大多数人类前列腺癌和前列腺上皮内瘤变 （别针）。相反，在正常前列腺组织中，GSTP1 基因的 CpG 岛 未甲基化并且该基因被表达。我们最近表明 胞嘧啶甲基化可以抑制 LNCaP 前列腺中 GSTP1 基因的表达 癌细胞，这种作用可能是由甲基介导的 胞嘧啶结合蛋白复合物 1(MeCP1) 样复合物。我们将阐明 进一步研究甲基化介导的 GSTP1 基因抑制机制 测定甲基 CpG 结合蛋白和组蛋白的体内结合 具有 GSTP1 基因启动子序列的脱乙酰酶。由于 GSTP1 甲基化是 前列腺癌发生的早期事件，有人提出罕见 具有高甲基化 GSTP1 启动子序列的前列腺细胞可能会进行克隆 由于接触致癌物质而扩张。 GSTP1 是 Jun 的抑制剂 N 末端激酶 (JNK) 活性和药理学或遗传操作 GSTP1 影响细胞增殖途径。目前尚不清楚是否 GSTP1表达的丧失会促进增殖和/或致瘤性 前列腺癌细胞。我们将确定是否具有增殖或致瘤性 人类前列腺癌细胞系 LNCaP 随 GSTP1 表达而变化 基因。 我们期望从研究中获得的结果将与 开发安全有效的药理学和基因靶向药物 人类前列腺癌患者的治疗方法，并将进一步推动我们的研究 了解 DNA 甲基化和癌症相关基因沉默。