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）：黑色素瘤的发病率在美国人群中迅速增加。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。我们的实验室已经产生的数据表明，视黄酸核受体，RAR-β 2，作为一个肿瘤抑制基因，它的沉默有助于视黄酸的抑制黑色素瘤细胞生长的能力的损失。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dhromatin结构将检查RAR-β 2启动子DNA甲基化，以及正常人黑素细胞和RAR-β 2表达降低的人黑色素瘤细胞中组蛋白修饰和染色质结构的RAR-β 2启动子相关变化。随后，我们将测量单独或组合的EGCG、染料木黄酮和丁酸盐改变人黑色素瘤细胞中这些表观遗传修饰的能力。选择这些饮食成分是因为它们能够改变癌细胞的表观遗传变化。它们也被证明可以抑制一些人类黑色素瘤细胞系的生长。如果这些饮食成分逆转了我们的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-β 2基因的重新表达和维甲酸对该基因的诱导恢复。最后，我们将测量单独或组合的EGCG、染料木黄酮和丁酸盐在我们的人黑色素瘤细胞系中抑制锚定依赖性/非依赖性生长和基底膜侵袭的能力。这些表型改变对营养素引起RAR β 2再表达的能力的依赖性将通过使用siRNA抑制RAR-β 2的再表达来测试。这些营养物改变RAR-β 2 siRNA处理的细胞中黑素瘤表型的能力的丧失将证明需要RAR-β 2再表达。这项探索性研究将为黑色素瘤细胞的营养表观遗传机制提供新的和潜在的重要数据。根据获得的结果，这项调查可以转化为营养研究与黑色素瘤的动物模型。