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Manipulation of epigenome turns off as many genes as it turns on

Agents believed to selectively "restart" genes that limit cancer's growth -- a potential treatment option already in early clinical studies -- instead turn off as many genes as they turn on, a team of researchers from the National Cancer Institute and Johns Hopkins has discovered.

"We don't know what effect all these changes might have, but it's clear that when scientists are looking only at the agents' effects on a particular gene or a few particular genes, they aren't seeing the whole picture," says Andrew Feinberg, M.D., M.P.H., King Fahd Professor of Medicine at Johns Hopkins. Their report appears in the October issue of Cancer Cell.

The research team probed the global effects of each of three approaches to unhooking methyl groups from genes' DNA. Cells normally use methyl groups to "mark" certain genes, indicating whether their instructions should or shouldn't be used for making proteins, but the marks are frequently disrupted in cancer cells.

For example, in cancer cells genes that normally stifle cell growth -- so-called tumor suppressor genes -- are shut down because extra methyl groups are hanging on to them. If these extra methyl groups could be removed, the thinking has gone, the gene could be restarted and the cancer slowed or stopped.

But the new work shows that while the agents tested do restart cancer-suppressing genes, they also knock methyl groups off other genes. Moreover, some of the unexpectedly affected genes are turned on, but an equal number -- hundreds -- of other genes are turned off.

The findings don't mean automatic failure for clinical trials of so-called demethylation agents, but they do indicate that careful attention should be paid to results of laboratory experiments and clinical trials that use the agents, since so many genes are affected, says Feinberg.

"It was kind of assumed that removing methyl groups would turn some genes on and others off, but the deactivation s
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
18-Oct-2004


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