Comparative Mechanisms of Cancer Chemoprevention

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DESCRIPTION (provided by applicant): The NIH Roadmap stipulates that epigenetics is a research priority. Unlike genetic changes associated with cancer, epigenetic changes are potentially modifiable, and dietary factors have been shown to "de-repress" epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. The overall long-term objectives of this P01 are to better understand the mechanisms by which beneficial epigenetic changes can be brought about by dietary agents, to identify and characterize epigenetic biomarkers that can be applied in the clinical setting, and to evaluate those biomarkers in preclinical and translational studies. With three well-integrated Projects and a complementary Epigenetic/Translational Biomarkers Core, this competing continuation addresses the application (and possible risks) of dietary indoles and isothiocyanates for cancer intervention, through comparative mechanism, biomarker, and preclinical models (lymphoma, prostate, colon, lung cancer), leading to translational studies of epigenetic biomarkers in human volunteers. The CENTRAL HYPOTHESIS is that sulforaphane (SFN) and indole-3-carbinol (ISC), and the cruciferous vegetables from which they derive, are effective chemopreventive agents because, in addition to their blocking activities during the initiation phase, they alter the pattern of histone modifications (acetylation, methylation, phosphorylation) and histone deacetylase (HDAC) activity in cancer cells, as well as DNA promoter methylation status, thereby de-repressing epigenetically silenced genes that regulate the cell cycle and apoptosis. E. Ho will investigate "Chemoprevention of prostate cancer, HDAC inhibition, and DNA methylation" (Project 1), D.E. Williams will study "Transplacental chemoprevention of lung tumors and lymphomas" (Project 2), and R.H. Dashwood will examine "Chemoprevention of colon cancer, HDAC inhibition, and histone status" (Project 3). The overall significance of the work is that it seeks to provide new epigenetic insights into the prevention and treatment of colon, prostate, and lung cancer, as well as lymphoma, which are listed consistently among the top causes of cancer-related deaths in the US. This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet.