Decitabine, a Demethylating Agent, Activates the Proteasome which Degrades DNA Methyltransferase

Abstract

Scientists are learning how a new class of anticancer drugs carries out its unusual way of fighting cancer. The drugs re-activate genes that normally protect against cancer but have been turned off. But the way the drugs were thought to work didn't explain many of their effects.

The research by investigators at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSU CCC-James), shows that the drugs cause the destruction of a protein that helps turn off the protective genes.

The findings give a new picture of how the drug, decitabine, works. They also suggest that decitabine will probably not be effective in those patients who are taking medications that interfere with the process that destroys the protein.

Decitabine is the most potent member of a new class of drugs known as DNA hypomethylating agents. These new drugs are used in a type of cancer treatment known as epigenetic therapy, which is now undergoing clinical trials testing, particularly for some types of leukemia. The findings are published online in the June issue of the journal Molecular and Cellular Biology.

DNA hypomethylating agents fight cancer by reversing a chemical process that turns off tumor-suppressor genes, which normally protect cells from becoming cancerous.

That process is known as methylation. It involves the gradual addition of chemical units known as methyl groups to genes. As the methyl groups accumulate, the gene gradually shuts down. Decitabine and other hypomethylating agents work by removing the methyl groups, enabling the gene to become active again.

Decitabine stops the methylation process by eliminating a protein known as DNA methyltransferase 1, an enzyme that adds methyl groups to DNA.

Until now, researchers believed that decitabine must first be incorporated into the cell's DNA before it can work. The DNA methyltransferase protein was then thought to join tightly with the DNA where the drug is incorporated, rendering the enzyme inactive.

"But that does not appear to be the case," says study leader Samson T. Jacob, Davis Professor in Cancer Research, professor of molecular and cellular biochemistry and of internal medicine, and co-director of the OSU CCC-James Experimental Therapeutics Program. "The drug can become incorporated into the cell's DNA, but that can take considerable time. In contrast, the drug destroys the transferase protein in cancer cells relatively quickly."

Jacob and his colleagues found that, once inside the cell, decitabine triggers a series of chemical reactions known as the proteasomal pathway, which degrades the transferase protein.

"Now that we know what is happening and how it is happening," Jacob says, "we can begin exploring ways to make this drug more effective."

Other OSU researchers involved in this study were Kalpana Ghoshal, who co-led the project; Jharna Datta; Sarmila Majumder; Shoumei Bai; Tasneem Motiwala; and Huban Kutay.

Funding from the National Cancer Institute and the National Institute of Environmental Health Sciences supported this research.

Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute is one of the nation's leading centers for research on the prevention, detection, diagnosis and treatment of cancer. The OSU CCC-James encompasses six interdisciplinary research programs and includes more than 200 investigators who generate over $95 million annually in external funding. It is a founding member of the National Comprehensive Cancer Network, and OSU's James Cancer Hospital is consistently ranked by U.S. News & World Report as one of America's best cancer hospitals.