AICR ScienceNow
Volume 20
Spring 2007

Epigenetics: A New Frontier in Cancer Research

It's not all in your genes. Researchers are increasingly unraveling clues as to diet's role in the new science of epigenetics, leading to major findings in cancer development and treatments.

For decades cancer has been known as a disease caused by genes undergoing mutations that trigger the growth of cancer cells. But a burgeoning field known as epigenetics is showing that many cancers may not be caused by mutations in genes, but by chemical modifications that alter how the genes function. Such modifications to genes are epigenetic - literally "on top of" or "related to" changes in the DNA sequence. And a growing body of evidence shows that epigenetic changes can be spurred by environmental factors, such as diet.

In the last 15 years, ever-advancing technology has helped researchers chip away at understanding the biochemical mechanisms at work in the cell. Researchers now know that epigenetic modifications influence gene expression and can thereby play an important role in the development of diseases, including cancer. For example, a tumor suppressor gene, which normally regulates cell growth and death, can be "turned off" or silenced by an epigenetic modification, rather than by a mutation of the gene itself.

Genes Affected by "Packaging"
There are two main epigenetic processes widely studied in relation to cancer, both relating to how DNA is packed in the cell's nucleus.

Within the nucleus, DNA coils tightly around "beads" of proteins called histones. The first process involves a cluster of chemicals - called a methyl group - that stick to particular sites on the DNA coil. Known as DNA methylation, the process of adding a methyl group to DNA can turn genes on and off, but it does not change the genes.

A second epigenetic process relates directly to the beads of proteins - the histones. When various molecules attach to histones it can alter how tight or loose the DNA strand is wound. A loosely coiled strand opens up more places on the DNA that methyl groups can attach; a tightly wound coil keeps more genes tucked away, not allowing methyl groups access to the DNA. (See figure.)

According to University of Nebraska researcher Judith Christman, Ph.D., who chaired sessions on epigenetics at AICR's annual conferences in
2005 and 2006, much current research is looking at how DNA methylation and histone modification interact during development. Dr. Christman notes that in both embryonic and cancer development, "we are trying to understand when these epigenetic modifications may be most susceptible to dietary or environmental effects."

Soy's Cancer Prevention via Epigenetics
An example of such research is that of Benito O. de Lumen, Ph.D., Professor of Nutritional Sciences and Toxicology at the University of California at Berkeley. Dr. de Lumen is studying lunasin, a peptide his laboratory discovered in soy in 1999 and subsequently found in barley and wheat. His laboratory research established that lunasin was effective in preventing skin cancer in mice through an epigenetic mechanism. Now, with funding from AICR, he is studying the effect of ingested lunasin in preventing prostate cancer in mice.

"Lunasin's mechanism of action seems to be quite different from that of other cancer-preventive compounds found in soy, such as phytoestrogens and protease inhibitors," Dr. de Lumen comments. Lunasin's mechanism is epigenetic because in cancer cells it disrupts a process involved in the DNA coil unwinding, without affecting the DNA sequence.

When lunasin is introduced to cancer cells, lunasin makes its way to the cell nucleus and changes the histones in a way that kills cancer cells while leaving normal cells intact. "Because the epigenetic mechanism that we are proposing is quite fundamental, we are predicting that lunasin would be preventive against many kinds of cancers in which [DNA-histone] modification is used by the carcinogen," he says.

Epigenetic Changes Can Be Inherited
Other research has shown that DNA methylation caused by nutrients was passed on to offspring, even though the gene's DNA sequence was unaltered. Randy Jirtle, Ph.D., of Duke University, described this research at AICR's 2006 annual meeting. Dr. Jirtle and his colleagues fed supplements containing vitamin B12, folic acid, choline and betaine (from sugar beets) to a group of pregnant mice with the agouti gene.

The agouti gene gives mice yellow fur and a predisposition to obesity, cancer and diabetes. The four nutrients promote methylation because they help donate methyl groups.

Most of the offspring of mice fed the diet rich in methyl donors produced babies born with brown coats that did not become fat. In contrast, most of the offspring of the control group of genetically identical mice had yellow coats and became obese.

Significantly, the researchers found that one or possibly several of the four nutrients caused the DNA strands in the treated mice to become methylated. The DNA methylation silenced the agouti gene controlling coat color and appetite. "This research opened the black box of how something that occurs literally at the very first one- to two-cell stage of development can affect disease susceptibility later," Dr.

Jirtle comments. "Epidemiological evidence in both humans and animal models has shown that there appear to be fetal origins of adult disease. But nobody knew how it happened. We showed absolutely that it was methylation. This was the first example of how the mother's diet can alter gene expression in her offspring by modifying the epigenome, not by mutating the gene itself."

Epigenetic Research Directions
Researchers are looking at epigenetic approaches to cancer therapy and prevention in several ways. One is to find ways to reactivate tumor-suppressor genes and restore normal cell function. A second approach is to combine treatment or dietary changes with chemotherapy drugs known to influence epigenetics to increase their efficacy.

Predicting cancer risk by identifying methylation changes is another focus of research. "We now have the capability to use microarrays to probe for changes in DNA methylation in different cells and tissues during early development and tumorigenesis," Dr. Christman says. "There is a huge potential for identifying early markers of epigenetic changes that influence health and longevity, and the potential to reverse the changes through diet or drugs."

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