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

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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.