RARbeta in Melanoma: Epigenetic Regulation by Nutrients

黑色素瘤中的 RARbeta：营养素的表观遗传调控

• 批准号: 7291022
• 负责人: Richard M. Niles
• 金额: $ 6.79万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291022
• 关键词: Address; Anchorage-Independent Growth; Animal Model; Basement membrane; Butyrates; Butyric Acid; Butyric Acids; Cancer and Nutrition; Cell Line; Cells; Chromatin Structure; Clinical; DNA Methylation; DNA Modification Process; Data; Dependency; Development; Dietary Component; Epigallocatechin Gallate; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Genistein; Growth; Histones; Human; Incidence; Investigation; Laboratories; Literature; Malignant Neoplasms; Measures; Mediating; Melanoma Cell; Metastatic Melanoma; Modification; Nutrient; Nutritional Study; Population; Proteins; Rate; Regulation; Reporting; Research Personnel; Resistance; Small Interfering RNA; Specimen; Structure; Testing; Translating; Tretinoin; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vertical Growth Phase; butyrate; cancer cell; dietary constituent; experience; gene induction; melanocyte; melanoma; progesterone 11-hemisuccinate-(2-iodohistamine); promoter; receptor; response; restoration; retinoic acid receptor beta 2; tumor; tumor growth

DESCRIPTION (provided by applicant): The incidence of melanoma is rapdily increasing in the US population. Data in the literature indicate that epigenetic changes contribute to the development and progression of melanoma. Our laboratory has generated data that suggests the retinoic acid nulcear receptor, RAR-beta2, acts a a tumor suppressor gene and that its silencing contributes to the loss of retinoic acid's ability to inhibit growth of melanoma cells. In this exploratory study, a team of scientsits with expertise in nutrition and cancer; DNA methylation; and dhromatin structure will examine RAR-beta2 promoter DNA methylation, and RAR-beta2 promoter- associated changes in histone modification and chromatin structure in normal human melanocytes and human melanoma cells having decreased expression of RAR-beta2.. Subsequently, we will measure the ability of EGCG, genistein and butyrate, alone or in combination, to alter these epigenetic modifications in the human melanoma cells. These dietary components were chosen for their reported ability to modify epigenetic changes in cancer cells. They also have been shown to inhibit the growth of some human melanoma cell lines. If these dietary constituents reverse epigenetic changes in our melanoma cell lines, we will determine if this results in the reexpression of the RAR-beta2 gene and restoration of retinoic acid induction of this gene. Lastly, we will measure the ability of EGCG, genistein and butyrate, alone or in combination to inhibit anchorage-dependent/independent growth and basement membrane invasion in our human melanoma cell lines. The dependency of these phenotypic alterations, on the ability of nutrients to cause reexpression of RARbeta2 will be tested by using siRNA to inhibit reexpression of RAR-beta2. Loss of the ability of these nutrients to alter the melanoma phenotpe in RAR-beta2 siRNA treated cells would demonstrate the requirement for RAR-beta2 reexpression. This exploratory study will provide new and potentially important data on nutrient epigenetic mechanisms in melanoma cells. Depending on results obtained, this investigation can be translated into nutritional studies with animal models of melanoma.

描述（由申请人提供）：美国人口中黑色素瘤的发病率正在迅速增加。文献中的数据表明表观遗传变化有助于黑色素瘤的发生和进展。我们实验室生成的数据表明，视黄酸核受体 RAR-β2 是一种肿瘤抑制基因，其沉默会导致视黄酸失去抑制黑色素瘤细胞生长的能力。在这项探索性研究中，一组具有营养和癌症专业知识的科学家； DNA甲基化；和染色质结构将检查 RAR-β2 启动子 DNA 甲基化，以及正常人黑色素细胞和 RAR-β2 表达降低的人黑色素瘤细胞中与 RAR-β2 启动子相关的组蛋白修饰和染色质结构的变化。随后，我们将测量 EGCG、染料木黄酮和丁酸盐单独或组合改变人类黑色素瘤中这些表观遗传修饰的能力 细胞。选择这些饮食成分是因为它们具有改变癌细胞表观遗传变化的能力。它们还被证明可以抑制某些人类黑色素瘤细胞系的生长。如果这些饮食成分逆转了黑色素瘤细胞系中的表观遗传变化，我们将确定这是否会导致 RAR-beta2 基因的重新表达以及该基因的视黄酸诱导恢复。最后，我们将测量 EGCG、染料木黄酮和丁酸盐单独或组合抑制人类黑色素瘤细胞系中贴壁依赖性/独立生长和基底膜侵袭的能力。这些表型改变对营养物引起RARβ2再表达的能力的依赖性将通过使用siRNA抑制RAR-β2再表达来测试。在 RAR-β2 siRNA 处理的细胞中，这些营养物质改变黑色素瘤表型的能力丧失将证明需要 RAR-β2 重新表达。这项探索性研究将为黑色素瘤细胞营养表观遗传机制提供新的、潜在的重要数据。根据获得的结果，这项研究可以转化为黑色素瘤动物模型的营养研究。