Cancer-Causing Gene Identified in Many Colon Cancers

Demonstrating that in spite of the large number of cancer-causing genes already identified, many more remain to be found, according to U.S. scientists, who have linked a previously unsuspected gene, CDK8, to colon cancer.

The discovery, made by researchers from the Dana-Farber Cancer Institute (Boston, MA, USA), of CDK8's role in cancer was made possible by new tools for assessing the activity of specific genes, according to the investigators of the new study. As these tools are additionally improved, the flow of newly discovered cancer genes is expected to increase, providing new avenues for therapy, the investigators predict. The findings were published online in the journal Nature on September 14, 2008.

"This study provides confirmation that many of the genes involved in cancer have yet to be identified,” remarked the study's senior author, William Hahn, M.D., Ph.D., from Dana-Farber and the Broad Institute of Harvard University (Cambridge, MA, USA) and the Massachusetts Institute of Technology (MIT, Cambridge, MA, USA). "When it comes to identifying gene targets for therapy, we've really only scratched the surface.”

The study is significant in another way, as well, the researchers indicated. Many of the abnormal proteins linked to cancer are known as transcription factors because they are able to "read” cell DNA and use that information for producing other cell proteins.

Although transcription factors are important regulators, this class of proteins has proven to be impossible to target with drugs. Genes that influence such transcription factors, however, make attractive targets for drugs, since they can potentially disrupt the cancer process and disable tumor cells. CDK8 is such a gene.

The new study started with a focus on a protein called ß-catenin, a transcription factor that is overactive in nearly all colorectal cancers. Although overactive ß-catenin plays a role in the initial formation of tumors, other genetic abnormalities must occur for tumors to become fully malignant.

To determine which genes control the production of ß-catenin and are involved in the proliferation of colon cancer cells, the researchers ran three screening tests. In the first two, they used RNA interference to deactivate more than a thousand genes one by one, and recorded the instances where ß-catenin activity decreased and the cells stopped growing. They then analyzed colon cancers for genes that had extra copies.

When the investigators examined where the results of the three tests overlapped, one gene stood out--CDK8, explained Dr. Hahn, who is also an associate professor of medicine at Harvard Medical School. The protein produced from CDK8 is part of the mediator complex, a conglomeration of proteins that serves as a bridge for compounds involved in gene transcription.

"This study demonstrates that blocking CDK8 interferes with the proliferation of colon cancer cells that have high levels of the CDK8 protein and overactive ß-catenin," Dr. Hahn said. "Drugs that target CDK8 may be very useful against tumors whose growth is driven by ß-catenin.”

Related Link:
Dana-Farber Cancer Institute