New gene-silencing enzyme discovered: Implications seen for treating aggressive cancers

April 14, 2002

PHILADELPHIA - Although the human genome is estimated to contain about 35,000 genes, only a fraction of these genes are turned on in a given cell type under normal circumstances. Precise control of gene expression is essential; many cancers have been linked to the improper activation of genes that should remain repressed, or silenced.

Now, researchers at The Wistar Institute report the identification of a new enzyme that is required for the silencing of certain genes. The enzyme functions by placing a molecular marker on a gene that causes the gene to be silenced. When this molecular marker is lost, certain genes may be improperly reactivated, which can result in cancer. Discovery of the enzyme could lead to new cancer therapies. A report on the research appears in the April 15 issue of Genes and Development.

"In this study we showed that when this enzyme is active at a particular gene, it places a molecular marker on the gene," says Frank J. Rauscher III, Ph.D., a professor at The Wistar Institute and deputy director of The Wistar Institute Cancer Center. "This molecular marker is crucial in silencing sets of genes."

The molecular marker is the methylation, or addition of a methyl group, to the DNA packaging proteins called histones on the gene that is to be silenced. When this molecular marker is lost, certain genes are no longer silenced but are instead reactivated, which may result in cancer. For instance, Rauscher notes that it has recently been shown that when you lose this molecular marker on a particular set of genes, a normally nonaggressive breast cancer can become very aggressive and metastatic.

"Now that we have found a new enzyme that is required for the silencing of certain genes," Rauscher says, "we believe it will be possible to create specific drugs that can either repress or activate gene expression through the targeting of this enzyme. This could lead to therapies for cancer, specifically for controlling the metastatic spread of cancer."

Rauscher says that his laboratory is now working to discover which genes in the human genome are silenced by this newly discovered enzyme. His research team is also interested in finding chemical inhibitors of this enzyme. Finally, they are studying breast, colon, and lung cancers to determine whether the gene that codes for this enzyme is mutated in these diseases.

In addition to senior author Rauscher, the lead author is David C. Schultz, Ph.D., formerly of The Wistar Institute and now with Case Western Reserve University, and co-authors are Kasirajan Ayyanathan, Ph.D., Dmitri Negorev, Ph.D., and Gerd G. Maul, Ph.D., all of The Wistar Institute. The research was supported by grants from the National Institutes of Health, the Irving A. Hansen Memorial Foundation, and The Susan G. Komen Breast Cancer Foundation. Early parts of this work were supported by the Pew Scholars Program in the Biomedical Sciences.
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The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center - one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.

News releases from The Wistar Institute are available to reporters by direct e-mail or fax upon request. They are also posted electronically to Wistar's home page (http://www.wistar.upenn.edu), to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science.

The Wistar Institute

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