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一个重要因素。饮食调整是降低癌症发病率或延缓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。 Indole-3-carbinol (I3C) 是十字花科蔬菜的关键活性成分，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物质可能与儿童和青少年癌症有关。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 I3C 可显着降低因侵袭性淋巴母细胞淋巴瘤引起的后代死亡率。然而，I3C 为胎儿提供这种癌症保护的机制尚不清楚。新证据表明，Cyp1b1 在该动物模型中淋巴瘤的发展中发挥着关键作用，并且该基因是其他癌症表观遗传控制的目标。因此，该提案的主要目标是确定膳食 I3C 如何改变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，3,3'-二吲哚甲烷 (DIM) 对 DBP 诱导的淋巴瘤没有保护作用，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（而非 DIM）会改变参与致癌作用的关键基因（包括人类 CYP1B1）的 DNA 甲基化状态。我们计划通过追求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 I3C、DIM 或甲基供体的母体饮食对人源化小鼠 CYP1B1 的表观遗传调节；2）通过 DNA 甲基化状态或组蛋白脱乙酰酶 (HDAC) 活性的改变，确定 I3C 在表观基因组水平上修饰的参与肿瘤发生的分子靶点。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点：使用人源化 CYP1B1 菌株的 DBP 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）来检查饮食I3C对整个人类基因组DNA甲基化的影响。拟议研究的成功完成将提供关于饮食 I3C 对表观基因组（特别是人类 CYP1B1）的影响以及这些靶标在癌症预防和抑制中的作用的新知识。拟议研究的结果可能会通过针对妊娠敏感期的表观基因组来导致癌症预防策略的范式转变。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期间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源性化合物（例如吲哚-3-甲醇）可以预防后代的儿童和成人癌症。然而，目前对吲哚-3-甲醇对胎儿发挥其癌症化学预防作用的机制缺乏了解，这引发了对其作为人类癌症预防和/或治疗剂的可能用途的疑问。

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.