CONTACT: JENNIFER CRONIN
2130 Medical Laboratories
Iowa City IA 52242
(319) 335-9917; fax (319) 335-8034
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
"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,"
P16INK4A is a broad-acting tumor suppressor gene.
Its methylation, deletion and mutation can be found in various tumor types,
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
"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
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.