Cancer prevention by indole-3-carbinol via modulation of the epigenome

通过调节表观基因组通过吲哚-3-甲醇预防癌症

基本信息

批准号：
7783782
负责人：
Abby D Benninghoff
金额：
$ 18.48万
依托单位：
UTAH STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7783782
关键词：
Acids Address Adult Adult Children Animal Model Animals Apoptosis BAX gene Brassica Breast Breast Feeding Broccoli - dietary Cabbage - dietary Cancer Model Cauliflower Cell Cycle Progression Cell Transplants Cell physiology Cells Chemoprevention Chemopreventive Agent Chemoprotection Child Childhood Colon Consumption CpG Islands Cytochrome P450 DNA Adducts DNA Methylation Data Development Diet Diet Modification Dietary Indole Dietary Phytochemical Disease Enzymes Epidemiologic Studies Epigenetic Process Exposure to Fetus Formaldehyde Frequencies Generations Genes Glucosinolates Goals Growth Health Histone Acetylation Histone Deacetylase Human Human Genome Incidence Indole-3-Carbinol Indoles Infant Knowledge Laboratories Lactation Lead Link Lung Lung Neoplasms Lymphoma Malignant Neoplasms Malignant neoplasm of prostate Metabolism Methionine Methylation Modification Molecular Target Mothers Mus Neonatal Onset of illness Pathway interactions Perinatal Exposure Phase Physical condensation Plants Play Pregnancy Prevention strategy Preventive Property Pyrenes Reaction Regulation Relative Risks Research Risk Role Skin Cancer T-Lymphocyte Testing Therapeutic Agents Thymic Lymphoma Thymus Gland Transplacental Carcinogenesis Transplantation Vegetables Woman Xenograft Model cancer cell cancer prevention cancer risk carcinogenesis chemical carcinogen cost cruciferous vegetable dietary supplements diindolylmethane environmental chemical feeding immunodeficient mouse model in utero in vivo Model lymphoblast methyl group middle age mortality mouse model neonate new technology novel offspring pregnant prevent programs protective effect public health relevance response tumorigenesis young adult

项目摘要

DESCRIPTION (provided by applicant): Diet is widely recognized as an important factor in lifetime cancer risk. Diet modification represents a safe and cost-effective strategy to decrease the incidence of cancer or delay the onset of the disease. The long-term goal of our research program is to develop a better understanding of how dietary phytochemicals can influence human health and disease. Indole-3-carbinol (I3C), a key active component of cruciferous vegetables, has been shown to be a remarkably effective cancer chemopreventive agent by reducing risk of lung, colon, breast and skin cancer. There is great concern that fetal exposure to environmental chemicals during pregnancy could be linked to childhood and young adult cancers. A recent study using a dibenzo(a,l)pyrene (DBP) transplacental mouse cancer model showed that maternal consumption of I3C during pregnancy and lactation markedly decreased offspring mortality due to aggressive lymphoblastic lymphoma. However, the mechanism by which I3C confers this cancer protection to the fetus is unknown. New evidence suggests that Cyp1b1 plays a critical role in the development of lymphoma in this animal model, and this gene is a target for epigenetic control in other cancers. Thus, the primary objective of this proposal is to determine how dietary I3C modifies the epigenome to decrease the overall risk of cancer. I3C is capable of donating to the methyl donor pool, thus increasing available methyl groups for DNA methylation. In contrast, 3,3'-diindolylmethane (DIM), which is not protective against DBP-induced lymphoma, is not likely to act via this mechanism because it is not a methyl donor molecule. This contrast provides a powerful experimental approach to test our hypothesis. We hypothesize that dietary I3C, but not DIM, alters the DNA methylation status of key genes involved in carcinogenesis, including human CYP1B1. We plan to accomplish our objective by pursuing the following specific aims: 1) investigate epigenetic modulation of CYP1B1 in humanized mouse by I3C-, DIM- or methyl donor-enriched maternal diets in mouse model of transplacental carcinogenesis, and 2) identify molecular targets involved in tumorigenesis that are modified by I3C at the level of the epigenome, either via alterations in DNA methylation status or activity of histone deacetylase (HDAC). To accomplish these aims, we will employ two in vivo models of lymphoma to evaluate methylation of human CYP1B1 and other potential epigenetic targets: the DBP transplacental mouse model using a humanized CYP1B1 strain and a human lymphoma cell xenograft model in scid mice. We will also employ new technology (CpG island microarrays) to examine effect of dietary I3C on DNA methylation in the entire human genome. Successful completion of the proposed research will provide new knowledge about the effect of dietary I3C on the epigenome, specifically human CYP1B1, and the role of these targets in cancer prevention and suppression. The findings of the proposed research could lead to a paradigm shift in cancer prevention strategies by targeting the epigenome during the sensitive period of gestation. PUBLIC HEALTH RELEVANCE: The fetus is a sensitive target for environmental compounds, and a significant portion of lifetime exposure to chemical carcinogens occurs during gestation and throughout breast feeding. Evidence suggests that maternal consumption of certain vegetables or plant-derived compounds, such as indole-3-carbinol, during pregnancy can prevent childhood and adult cancers in offspring. However, the current lack of understanding of the mechanisms by which indole-3-carbinol exerts its cancer chemopreventive effects to the fetus raises questions about its possible utility as a preventive and/or therapeutic agent for human cancer.

描述（由申请人提供）：饮食被广泛认为是终生癌症风险的重要因素。饮食修改代表了一种安全且具有成本效益的策略，以减少癌症的发生率或延迟疾病的发作。我们的研究计划的长期目标是更好地了解饮食植物化学物质如何影响人类健康和疾病。通过降低肺，结肠，乳腺癌和皮肤癌的风险，吲哚-3-甲醇（I3C）是十字花科蔬菜的关键活性成分，是一种非常有效的癌症化学预防剂。人们非常担心怀孕期间胎儿对环境化学物质的暴露可能与童年和年轻的成人癌症有关。最近使用Dibenzo（A，L）Pyrene（DBP）移植小鼠癌症模型的研究表明，孕妇在妊娠期间对I3C的食用和泌乳的消耗显着降低了由于侵袭性淋巴细胞淋巴瘤而导致的后代死亡率。但是，I3C对胎儿保护这种癌症保护的机制尚不清楚。新的证据表明，CYP1B1在该动物模型的淋巴瘤发展中起着至关重要的作用，该基因是其他癌症表观遗传控制的靶标。因此，该提案的主要目的是确定饮食I3C如何修饰表观基因组以降低癌症的总体风险。 I3C能够向甲基供体池捐赠，从而增加可用的甲基进行DNA甲基化。相比之下，没有保护DBP诱导的淋巴瘤的3,3'-二迪丁烷基甲烷（DIM）不太可能通过该机制起作用，因为它不是甲基供体分子。这种对比提供了一种强大的实验方法来检验我们的假设。我们假设该饮食I3C（但不是昏暗）改变了包括人CYP1B1在内的癌变的关键基因的DNA甲基化状态。我们计划通过追求以下特定目的来实现目标：1）通过I3C，dim或dim或甲基甲基供体增强的孕产妇饮食在人源化小鼠中的表观遗传调节中的表观遗传调节，在移植型癌变的小鼠模型中，以及2）鉴定在肿瘤中涉及的分子量的分子靶标涉及的分子靶标，该型号通过I3级甲基元素进行了调整，使甲基级别的epyy级别或甲基级别的层次变化。组蛋白脱乙酰基酶（HDAC）。为了实现这些目标，我们将采用两种体内淋巴瘤模型来评估人CYP1B1的甲基化和其他潜在的表观遗传靶标：使用人源化CYP1B1菌株和SICID小鼠中人类淋巴瘤细胞的DBP移植小鼠模型。我们还将采用新技术（CPG岛微阵列）来检查饮食I3C对整个人类基因组中DNA甲基化的影响。拟议研究的成功完成将提供有关饮食I3C对表观基因组（特别是人CYP1B1）的影响的新知识，以及这些靶标在预防癌症预防和抑制中的作用。拟议的研究的发现可能会在妊娠敏感时期靶向表观基因组，从而导致预防癌症预防策略的范例。公共卫生相关性：胎儿是环境化合物的敏感靶标，在妊娠期间和整个母乳喂养过程中，终生暴露于化学致癌物。有证据表明，在怀孕期间，孕产妇食用某些蔬菜或植物来源的化合物，例如吲哚-3-甲醇，可以预防儿童和后代的成年癌症。然而，目前对吲哚-3-甲醇对胎儿施加癌症化学预防作用的机制的理解缺乏理解，这引发了有关其作为人类癌症的预防和/或治疗剂的可能效用的问题。