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Release: Oct. 5, 1999

UI findings indicate DNA methylation process may lead to oral cancer

IOWA CITY, Iowa — Just like a light switch, a process known as cytosine methylation can turn off expression of tumor suppressor genes and lead to oral cancer, according to University of Iowa Health Care research findings.

"During cancer development, the normal control of cytosine methylation is lost, and DNA can become aberrantly methylated," explained Frederick Domann, Ph.D., UI associate professor of radiology. "When this happens to a tumor suppressor gene, it switches off its expression and contributes to cancer progression."

For some time now cancer researchers have focused on tumor suppressor genes in an attempt to answer the question of how cancer grows and spreads. When they work properly, tumor suppressor genes do just what their name suggests: they suppress cancer. However, if something disrupts the genes, the cancer grows and stretches into other areas of the body.

Classical genetics has shown that mutations and deletions of these tumor suppressor genes contribute to malignancy. However, another mechanism, DNA methylation, can inactivate tumor gene expression as well, Domann said. This methylation phenomenon is the focus of Domann's lab investigations. Methylation is the addition of single carbon atoms to specific target sites within the DNA.

Cytosine, one of the four nucleotides in DNA, is the only base that can be methylated normally by a cell's enzymatic machinery. Cytosine is normally methylated in cells at certain positions and not others. Carcinogenesis alters the pattern of cytosine methylation, which contributes to altered patterns of gene expression in cancer.

Based on the interest of one of his then post-doctoral fellows, D. Thane Cody II, M.D., currently assistant professor of surgery at Southern Illinois University, Domann and his team began investigating whether aberrant methylation contributed to oral cancer tumors. There were more than 28,000 new cases of oral cancer in the United States in 1995, resulting in more than 8,000 deaths.

Cody had identified an oral cancer cell line that had lost expression of the tumor suppressor gene p16INK4A but in which the gene was still intact. Because the gene was still intact, the investigators knew that the cell line had not suffered any gross tumor suppressor gene deletion and that methylation might be to blame for the cancer.

To test their hypothesis, the researchers isolated DNA from normal human oral keratinocytes and from the cancer cell line.

"We found a really striking difference in the methylation patterns of cytosine," Domann said. "In the normal human oral keratinocytes that had p16 expression, we found there was virtually no cytosine methylation, and the cancer cells that lacked p16 expression were nearly completely methylated."

Domann and his research team plan to do additional methylation studies to screen other oral cancer cell lines.

"We think that this might be a general mechanism in oral cancers, as well as in other cancers, for inactivating this gene locus," Domann said.

P16INK4A is a broad-acting tumor suppressor gene. Its methylation, deletion and mutation can be found in various tumor types, Domann said.

Although Domann stressed that the clinical relevance of his lab's findings is still years away, aberrant cytosine methylation eventually can be corrected. Ezymes in the cell, called DNA methyltransferase, mediate methylation.

"Any process that is mediated by an enzyme has the potential to be pharmacologically affected," Domann said. "Those enzymes can be targeted by drugs that are designed to inhibit the active sites for those enzymes."

The findings of Domann's research team appeared in a recent issue of the peer-reviewed European Journal of Cancer, Oral Oncology. Funding from the National Institutes of Health helped support this research.

In addition to Domann and Cody, the other researchers involved included Yuanhui Huang, Ph.D., currently a postdoctoral research associate at Parke-Davis Pharmaceuticals; Christine J. Darby, research assistant in the UI Free Radical & Radiation Biology Graduate Program; and Georgia K. Johnson, D.D.S., UI professor of dentistry, who works in the College of Dentistry's Dows Institute.

University of Iowa Health Care describes the partnership between the UI College of Medicine and the UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide.