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

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。改变饮食是降低癌症发病率或延缓疾病发病的一种安全且成本效益高的策略。我们研究计划的长期目标是更好地了解饮食中的植物化学物质如何影响人类健康和疾病。吲哚-3-甲醇(I3C)是十字花科蔬菜中的关键活性成分，通过降低肺癌、结肠癌、乳腺癌和皮肤癌的风险，已被证明是一种非常有效的癌症化学预防药物。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年轻人的癌症有关。最近一项使用二苯并(a，L)芘(DBP)经胎盘的小鼠癌症模型的研究表明，母亲在孕期和哺乳期摄入I3C显著降低了由侵袭性淋巴母细胞淋巴瘤引起的子代死亡率。然而，I3C赋予胎儿这种癌症保护的机制尚不清楚。新的证据表明，在这种动物模型中，CYP1B1在淋巴瘤的发展中起着关键作用，该基因是其他癌症表观遗传控制的靶点。因此，这项建议的主要目标是确定饮食I3C如何修改表观基因组以降低总体癌症风险。I3C能够向甲基供体池捐赠，从而增加可用于DNA甲基化的甲基基团。相比之下，对DBP诱导的淋巴瘤没有保护作用的3，3‘-二吲哚甲烷(DIM)不太可能通过这种机制发挥作用，因为它不是甲基供体分子。这种对比提供了一种强有力的实验方法来检验我们的假设。我们假设饮食中的I3C，但不是DIME，改变了包括人类细胞色素P1B1在内的致癌关键基因的DNA甲基化状态。我们计划通过追求以下特定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I3C-、DIM-或甲基供体丰富的母体饮食对人源化小鼠CYP1B1的表观遗传学调控；2)在表观基因组水平上识别I3C修饰的肿瘤发生的分子靶点，无论是通过DNA甲基化状态的改变还是组蛋白脱乙酰酶(HDAC)活性的改变。为了实现这些目标，我们将使用两个体内淋巴瘤模型来评估人类CYP1B1和其他潜在表观遗传学靶点的甲基化：使用人源化CYP1B1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。我们还将使用新技术(CpG岛微阵列)来检测饮食I3C对整个人类基因组DNA甲基化的影响。这项拟议研究的成功完成将提供有关饮食I3C对表观基因组的影响，特别是人类CYP1B1的新知识，以及这些靶点在预防和抑制癌症中的作用。这项拟议的研究结果可能会导致癌症预防策略的范式转变，在怀孕的敏感时期以表观基因组为靶点。公共卫生相关性：胎儿是环境化合物的敏感目标，一生中接触化学致癌物的很大一部分发生在妊娠和整个哺乳过程中。有证据表明，孕妇在怀孕期间食用某些蔬菜或从植物中提取的化合物，如吲哚-3-甲醇，可以预防儿童和成年后代患癌症。然而，目前对吲哚-3-甲醇对胎儿发挥癌症化学预防作用的机制缺乏了解，这引发了人们对其作为人类癌症预防和/或治疗剂的可能效用的质疑。

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.