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Research Newsletter-Spring/Summer 2010

EPIGENETICS



Rod Dashwood, Ph.D.
LPI Principal Investigator
Director, LPI Cancer Chemoprotection Program


"Epigenetics" has finally arrived front-and-center on the popular landscape. A recent cover of Time magazine showed an image of doublestranded DNA being unzipped next to the words, "Why your DNA isn't your destiny". The cover stated: "The new science of epigenetics reveals how the choices you make can change your genes – and those of your kids". Just how "new" this science really is can be debated, since it likely goes back to Darwin and Lamarck and opposing views of nature versus nurture. Whereas Darwin argued that incremental changes underlie the process of natural selection and survival-of-the fittest, Lamarck postulated that some traits were acquired within a lifetime due to environmental pressures. The Time article cited the example of Norrbotten county, Sweden. This cold and desolate area historically has been associated with periods of feast-and-famine, and research has shown that boys who went from normal eating to gluttony in a single season produced sons and grandsons who lived shorter lives. Another well-known example is the agouti mouse, which is fat, has a yellow coat, and is prone to cancer and diabetes. If the diet given to female agouti mice before conception is changed by adding chemicals called methyl donors (e.g., folate), the offspring have brown coats and are slim, despite having the same agouti gene sequence. Offspring of the mice fed their usual diet look like their parents. How might such rapid changes occur, and in a trans-generational manner? The answer seems to lie within the realm of epigenetics.

Epigenetics is the science that seeks to explain how changes in gene expression can occur without changes in the underlying DNA sequence. For example, a central theme in the cancer research field has been that mutations or large-scale chromosome rearrangements can alter the DNA sequence of key genes that regulate the fate of cells. If a gene normally expresses a protein that acts as a "brake", and this gene is mutated, then the corresponding dysfunctional protein no longer blocks unrestrained cell growth, which is a hallmark of cancer. Such tumor suppressor genes, however, also may have a normal DNA sequence, and yet the gene is aberrantly silenced in cancer. One way this can occur is by the addition to DNA of methyl groups. If these methyl groups accumulate on the 'start' region of the gene, the complex cellular machinery needed to turn on that gene is disrupted. The cellular machinery also can be blocked from even accessing the DNA in the first place. DNA is not naked in a cell but is surrounded by proteins called histones, which dynamically open and close to permit access to DNA at the right time and place. In cancers, over-expression of an enzyme called histone deacetylase (HDAC) leads to acetyl groups being removed from histone proteins, tightening their interactions with the DNA, and thereby switching off tumor suppressor genes. In essence, the "brake" is turned off, and cells continue to replicate without restraint.

Drugs that inhibit HDAC have shown promise in the clinic as therapeutic agents. They cause aberrantly silenced genes to be turned back on, thereby triggering cancer cells to commit suicide, also known as apoptosis. An exciting adjunct to this work is that some dietary constituents also have the ability to act as HDAC inhibitors. Metabolism of food and its individual constituents generates compounds like butyrate, sulforaphane, organosulfur and organoselenium compounds, and indole-3-carbinol derivatives that inhibit HDAC activity and block cancer cell growth. These themes are being developed in a newly funded $8.45 million program project grant from the National Cancer Institute (NCI), entitled "Comparative Mechanisms of Cancer Chemoprevention", which has the following central hypothesis:

"Sulforaphane, indole-3-carbinol, and the cruciferous vegetables from which they derive are effective dietary chemopreventive agents because they alter the pattern of histone modifications (acetylation, methylation, phosphorylation) and 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."

NIH Grant Schematic

LPI investigators Drs. Emily Ho, David Williams, and I will lead three integrated projects that focus on dietary chemoprotection strategies for cancers of the prostate, lung, and colon, as well as lymphomas, and include transgenerational studies in mice. All three projects use facilities and scientific expertise in the centralized Epigenetic/Translational Biomarkers (ETB) Core, headed by Dr. Christiane Löhr. Reporting duties to the NCI will involve an Administrative Core overseen by me, as Program Director. An important and exciting aspect of this work is that it will proceed to clinical trials with human volunteers, testing several of the epigenetic hypotheses in the context of real-world food intake patterns. LPI investigators have been at the leading-edge of research in this area for several years. With this new grant, we hope to go much further along the road to understanding the complex interactions between diet, epigenetics, and cancer prevention.

Last updated June 2010