Strategic Communication and Public Relations

Mysterious gene transcripts after cancer therapy

No. 33 | 12/06/2017 | by Rei/Koh

Drugs that are used in cancer therapy to erase epigenetic alterations in cancer cells simultaneously promote the production of countless mysterious gene transcripts, scientists from the German Cancer Research Center (DKFZ) now report in Nature Genetics. The substances activate hidden regulatory elements in DNA. The unusual gene activity has the potential to stimulate the immune system – a previously unnoticed effect that may increase the effect of therapeutic agents.

© Schuster, DKFZ

Tumor suppressor genes protect cells from malignant transformation. If they are turned off as a result of chemical modifications in DNA, called epigenetic labels, this contributes to the development of cancer. As opposed to gene mutations, these epigenetic changes are reversible and it is possible to use specific drugs to erase them.

"This has been successfully done for years now in various cancers such as acute myeloid leukemia and myelodysplastic syndrome," said Christoph Plass from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg. He added that it has also been proven that dangerous labels such as on tumor suppressor genes can be removed in this way. "However, the agents pass over the DNA like a lawn mower and remove practically all labels," said Plass, who also serves as a research coordinator within the German Cancer Consortium (DKTK). "And so far nobody has studied in detail what effect this has on the tumor cells."

Plass and his co-workers have now pursued this question in collaboration with colleagues from the U.S.A. Using genome-wide analyses, the scientists discovered that countless mysterious gene transcripts arise in the wake of treatment. This is due to an activation of specific regulatory elements in DNA, called promoters, which have been largely unnoticed so far. "There is total chaos in the treated cancer cells – we hadn't expected that," said David Brocks, who is one of the first authors of the study.

A closer look has shown that the activated regulatory elements originate from viruses that inserted themselves into the genome in the ancient past. However, they were turned off in the course of evolution, thus becoming normal components of DNA.

Protein fragments that form on the basis of these peculiar gene transcripts have the potential to be recognized by the immune system and, thus, to stimulate the immune system. This might increase the effectiveness of drugs that are being used. "Now we have to investigate whether this effect can be used specifically to improve therapy," Plass said. And yet another aspect: "These gene transcripts might be useful as biomarkers to examine whether an epigenetic therapy is effective and reasonable in the individual patient."

David Brocks, Christopher R. Schmidt, Michael Daskalakis, Hyo Sik Jang, Nakul M. Shah,Daofeng Li, Jing Li, Bo Zhang, Yiran Hou, Sara Laudato, Daniel B. Lipka, Johanna Schott, Holger Bierhoff, Yassen Assenov, Monika Helf, Alzbeta Ressnerova, Md Saiful Islam, Anders M. Lindroth, Simon Haas, Marieke Essers, Charles D. Imbusch, Benedikt Brors, Ina Oehme, Olaf Witt, Michael Lübbert, Jan-Philipp Mallm, Karsten Rippe, Rainer Will, Dieter Weichenhan, Georg Stoecklin, Clarissa Gerhäuser, Christopher C. Oakes, Ting Wang, und Christoph Plass: DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats. Nature Genetics, 2017, DOI: 10.1038/ng.3889

An image for this press release is available at:
http://www.dkfz.de/de/presse/pressemitteilungen/2017/bilder/DNA-Methylierung_Quelle_Schuster_DKFZ.jpg

Note on use of images related to press releases
Use is free of charge. The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) permits one-time use in the context of reporting about the topic covered in the press release. Images have to be cited as follows: "Source: Schuster, DKFZ".
Distribution of images to third parties is not permitted unless prior consent has been obtained from DKFZ's Press Office (phone: ++49-(0)6221 42 2854, E-mail: presse@dkfz.de). Any commercial use is prohibited.

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.

Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Tumour Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

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