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

• 批准号: 7661019
• 负责人: Abby D Benninghoff
• 金额: $ 16.08万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661019
• 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

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身癌症风险的重要因素。饮食调整是降低癌症发病率或延迟疾病发作的安全且具有成本效益的策略。我们研究计划的长期目标是更好地了解膳食植物化学物质如何影响人类健康和疾病。吲哚-3-甲醇（I3 C）是十字花科蔬菜的一种重要活性成分，已被证明是一种非常有效的癌症化学预防剂，可降低肺癌、结肠癌、乳腺癌和皮肤癌的风险。人们非常担心，胎儿在怀孕期间接触环境化学品可能与儿童和青年癌症有关。最近一项使用二苯并（a，l）芘（DBP）经胎盘小鼠癌症模型的研究表明，母亲在怀孕和哺乳期间摄入I3 C显著降低了由于侵袭性淋巴母细胞淋巴瘤引起的后代死亡率。然而，I3 C赋予胎儿这种癌症保护的机制尚不清楚。新的证据表明，Cyp 1b 1在这种动物模型中淋巴瘤的发展中起着关键作用，并且该基因是其他癌症中表观遗传控制的靶点。因此，该提案的主要目标是确定膳食I3 C如何修饰表观基因组以降低癌症的总体风险。I3 C能够贡献给甲基供体库，从而增加用于DNA甲基化的可用甲基。相比之下，对DBP诱导的淋巴瘤没有保护作用的3，3 '-二吲哚基甲烷（DIM）不太可能通过这种机制起作用，因为它不是甲基供体分子。这种对比提供了一个强有力的实验方法来测试我们的假设。我们推测，饮食中的I3 C，而不是DIM，改变了参与致癌作用的关键基因的DNA甲基化状态，包括人类CYP 1B 1。我们计划通过实现以下具体目标来实现我们的目标：1）在经胎盘致癌的小鼠模型中研究富含I3 C、DIM或甲基供体的母体饮食对人源化小鼠中CYP 1B 1的表观遗传调节，和2）鉴定在表观基因组水平上被I3 C修饰的涉及肿瘤发生的分子靶标，通过DNA甲基化状态或组蛋白脱乙酰酶（HDAC）活性的改变。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CYP 1B 1和其他潜在表观遗传靶点的甲基化：使用人源化CYP 1B 1菌株的DBP经胎盘小鼠模型和scid小鼠中的人淋巴瘤细胞异种移植模型。我们还将采用新技术（CpG岛微阵列）来研究膳食I3 C对整个人类基因组中DNA甲基化的影响。成功完成拟议的研究将提供有关饮食I3 C对表观基因组，特别是人类CYP 1B 1的影响的新知识，以及这些靶点在癌症预防和抑制中的作用。拟议研究的结果可能会导致癌症预防策略的范式转变，通过在妊娠敏感期靶向表观基因组。公共卫生相关性：胎儿是环境化合物的敏感目标，一生中暴露于化学致癌物的很大一部分发生在妊娠期和整个母乳喂养期间。有证据表明，母亲在怀孕期间食用某些蔬菜或植物衍生化合物，如吲哚-3-甲醇，可以预防后代的儿童和成人癌症。然而，目前缺乏对吲哚-3-甲醇对胎儿发挥其癌症化学预防作用的机制的了解，这引起了关于其作为人类癌症的预防和/或治疗剂的可能效用的问题。