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: 7179001
• 负责人: Richard M. Niles
• 金额: $ 7万
• 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/7179001
• 关键词: chromatin; epigenetics; human; melanoma

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展和发展。我们的实验室生成的数据表明，维甲酸nulcear受体RAR-BETA2作用于A肿瘤抑制基因，并且其沉默导致视黄酸抑制黑色素瘤细胞生长的能力的丧失。在这项探索性研究中，一群在营养和癌症方面具有专业知识的分数； DNA甲基化；和脱染色质结构将检查RAR-BETA2启动子DNA甲基化，以及RAR-BETA2启动子 - 组蛋白改性和染色质结构在正常人黑色素细胞和人类黑色素瘤细胞中具有降低RAR-BETA2的表达的变化。细胞。选择了这些饮食成分，以据报道其修饰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黑色素瘤细胞系的生长。如果这些饮食成分反向我们黑色素瘤细胞系的表观遗传学变化，我们将确定这是否导致RAR-BETA2基因的重新表达并恢复该基因的视黄酸诱导。最后，我们将单独或组合EGCG，染料木黄酮和丁酸酯和丁酸酯的能力来抑制人类黑色素瘤细胞系中锚定依赖性/独立生长和基底膜侵袭的能力。这些表型改变的依赖性，对养分引起rarbeta2重新表达的能力的依赖性将通过使用siRNA抑制RAR-BETA2的重新表达来测试。这些营养素改变RAR-BETA2 siRNA处理细胞中黑色素瘤表的能力的丧失将证明对RAR-BETA2重新表达的要求。这项探索性研究将提供有关黑色素瘤细胞中营养表观遗传机制的新的潜在重要数据。根据获得的结果，该研究可以通过黑色素瘤动物模型转化为营养研究。