Surprise Finding May Lead to Drugs for Treating Ewing Sarcoma

Cancer researchers have uncovered a previously unknown molecular function for the EWS/FLI fusion gene that may lead to the development of drugs to treat Ewing sarcoma, an often-fatal cancer of children and young adults.

Genetic exchange between chromosomes can cause cells to become cancerous, and about 85% of Ewing's sarcoma cases are the result of a translocation between chromosomes 11 and 22, which fuses the EWS gene of chromosome 22 to the FLI1 gene of chromosome 11. EWS/FLI then functions as the master regulator for cancer development.

Investigators at the University of Utah (Salt Lake City, USA) studied the interaction of EWS/FLI and the enzyme lysine specific demethylase (LSD-1), a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone three, lysines four and nine (H3K4 and H3K9).

The investigators reported in the November 26, 2012, online edition of the journal Oncogene that the EWS/FLI/LSD-1 combination blocked certain gene activities, which prompted development and spread of Ewing sarcoma cells. This finding complemented earlier results that showed that binding to DNA by the protein encoded by EWS/FLI led to development of Ewing sarcoma.

Recently discovered LSD-1 inhibitors were found to block growth of Ewing sarcoma cells in culture, and studies are to be extended to animal models.

"This makes LSD-1 an important target for the development of new drugs to treat Ewing sarcoma," said senior author Dr. Stephen Lessnick, professor of pediatrics at the University of Utah. "We think it may play a larger role in Ewing sarcoma than simply turning off a handful of genes, and we are looking into that."

"For a long time, we have known that EWS/FLI works by binding to DNA and turning on genes that activate cancer formation," said Dr. Lessnick. "It was a surprise to find out that it turns genes off as well. The beauty, if there is anything beautiful about a nasty disease like this, is that if we can inhibit EWS/FLI, we can inhibit this cancer, because EWS/FLI is the master regulator of Ewing sarcoma."

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