At the time, the scientists noted that the enzyme appeared to fit into the same extended enzyme family that includes monoamine oxidases, psychoactive enzymes that oxidize dopamine and norepinephrin. Inhibitors of these enzymes have long been used to treat depression, certain other psychiatric and emotional disorders, and Parkinson's disease.
Now, in a study published online today in the June 26 issue of Chemistry & Biology, Shiekhattar and his team show that the enzyme is itself a target for certain monoamine oxidase inhibitors used to treat depression. One member of this family of drugs in particular, called tranylcypromine (brand name Parnate®, manufactured by GlaxoSmithKline), was seen to inhibit the enzyme most strongly. The findings suggest that these anti-depressive drugs may have additional applications in other medically relevant areas.
For example, Shiekhattar notes that the enzyme studied exists in a complex with another type of gene-regulating enzyme that has been implicated in the development of cancer. Inhibitors of that second enzyme are currently in clinical trails as cancer therapies.
"Might particular monoamine oxidase inhibitors, currently used primarily to treat depression, have anti-cancer activity too?" Shiekhattar says. "Our findings indicate this could be the case, and we are currently screening these drugs against many different types of cancer to answer that question."
Because the primary role of the enzyme is to repress sets of related genes, many other areas of potential influence for the monoamine oxidase inhibitors are possible too, according to Shiekhattar. At the very least, he says, the drugs will likely prove to be useful laboratory tools for answering fundamental questions about genetic expression.
The enzyme in question is called BHC110/LSD1, and it was the first human histone demethylase identified. The enzyme's function is to remove methyl groups from small molecules called histones to modify them in ways that trigger gene repression. The second enzyme found in complex with BHC110/LSD1, acts in a similar way. Called a deacetylase, this enzyme removes acetyl groups from histones to repress gene expression.
In the body's scheme for safely storing genes away until needed, DNA is tightly looped around the histones, kept secure by enzymes similar to the ones studied by the Wistar team until made accessible by the activity of other enzymes responsible for gene expression. Eight histones comprise a nucleosome, and long strings of nucleosomes coil in turn into chromatin, the basic material of chromosomes.
The lead author on the Chemistry & Biology study is Min Gyu Lee. Christopher Wynder is a coauthor. Additional coauthors at the University of Pennsylvania School of Medicine are Dawn M. Schmidt and Dewey G. McCafferty. Senior author Ramin Shiekhattar is a professor in two programs at Wistar, the gene expression and regulation program and molecular and cellular oncogenesis program. Support for the research was provided by the National Institutes of Health.
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, such as AIDS and influenza. 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 focused on basic and translational research. Discoveries at Wistar have led to the creation of vaccines for such diseases as rabies, rubella, and rotavirus; significant insights into the mechanisms of skin, brain, breast, lung, and prostate cancers; and the development of monoclonal antibodies and other important research technologies and tools. The Wistar Institute: Today's Discoveries - Tomorrow's Cures. On the web at www.wistar.org.