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uni'wissen 01-2014_ENG

Schüle’s research group found out that LSD1 interacts with the so-called androgen receptor. This receptor activates genes responsible for growth and plays a key role in the development of prostate cancer. The aim of many prostate cancer therapies is thus to block the androgen receptor. After spending a certain time under such therapies, however, some patients develop a resistance to the anti-androgen hormone: The blocking fails, and the cancer continues to spread. LSD1 could be the solution for the future, because tests with cell cultures have shown that inhibiting the enzyme blocks the androgen receptor–depend- ent growth of the tumor. Interrupting the Chain of Events Schüle and other researchers at the University of Freiburg and the collaborative research center have discovered a second approach for fighting prostate cancer: “We have identified a new mechanism that shows how LSD1 could lead to prostate tumors in interaction with the androgen receptor.” At the root of the disease is a complex process involving several epigenetic enzymes. The enzymes that add a methyl group to the chromatin do the same thing to LSD1. The his- tone-demethylase becomes methylated itself. This gives it another surface that attracts a further epigenetic enzyme. This new enzyme binds to LSD1 and causes the condensed chromatin structure to open, allowing transcription factors to reach the androgen receptor–dependent genes more easily. These genes are activated, giving rise to uncontrolled cell growth. “If we could inter- rupt this chain of events, we could impede the growth of the tumor,” explains Schüle. “We have created a three-dimensional x-ray crystal struc- ture of the complex of LSD1 with the epigenetic enzyme.” The scientists can use this model to draw more precise conclusions concerning the surfaces of the two epigenetic enzymes and the interaction between them. “We know what the key and the lock look like. Now we can design the inhibitors to block this bond.” On the lookout for proteins: Roland Schüle’s research group is studying the epigenetic regulation mechanisms of prostate cancer. Photos: Patrick Seeger The photographs show various cultures with fat cells (the fat is dyed red). The cultures in the photos on the right contain a substance that inhibits the epigenetic enzyme LSD1, thus blocking fat formation. Photos: Delphine Duteil 1010