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Surprising enzyme function discovered in tumour development

(Vienna, 3 November 2010) In an interdisciplinary cooperation project, three research groups at MedUni Vienna and Max F. Perutz Laboratories have made surprising discoveries on the growth of malignant tumours which will enable new and particular effective therapeutic approaches.

Researchers at MedUni Vienna have been dealing with the mode of action of histone deacetylases, in particular HDAC1, for a long time. Histone deacetylases – or HDACs for short – are a group of enzymes which have a major influence on cell behaviour and are therefore also attributed a decisive role in the development of tumours. HDAC inhibitors – substances which suppress the activity of these enzymes in the cell – therefore represent a promising group of substances in cancer therapy and are currently already being tested in clinical trials. As part of a project funded by the Austrian Science Fund (FWF), scientists at Max F. Perutz Laboratories (MFPL) and the Medical University of Vienna have now made surprising findings which were also recently published in the internationally renowned specialist magazine "EMBO Journal".

In the project the research groups wanted to clarify the precise role of individual HDACs in the development of cancer because so far these have not been studied much. "Among the enzymes of the HDAC group we had the suspicion that HDAC1 in particular was responsible for the aggressiveness of tumours because it is important for regulating cell growth," explains Ao. Univ. Prof. Dr. Christian Seiser from the Division of Molecular Genetics and head of the research group at MFPL. The researchers examined the function of the enzymes in teratomas, a special group of tumours which form mainly in the gametes – ovaries and testicles – and become malignant in many cases.

To the surprise of the researchers it became apparent that the teratomas became more malignant when the production of HDAC1 was suppressed. This discovery disproves the previous assumption that excess production of HDAC1 may generally be responsible for uncontrolled tumour growth.

In the project Christian Seiser is also working together with the research groups of university lecturer Ao. Univ. Prof. Mag. Dr. Wolfgang Mikulits at the Cancer Research Institute and Ao. Univ. Prof. Dr. Lukas Kenner from the Clinical Institute of Pathology at the Medical University of Vienna. "We examined the role of the enzymes using mouse models, and thanks to the cooperation with clinical research groups we were also able to compare the results with human tumour cells." Among those responsible here was the group of Lukas Kenner together with the teratoma specialist Ao. Univ. Prof. Dr. Martin Susani, which observed the same effect in its tests: the more aggressive the human teratoma, the lower was the existing amount of HDAC1.

The research results could now make it possible to use HDAC1 as a new 'marker' for the potential aggressiveness of tumours. A possibly malignant tumour could therefore be detected at a very early stage. At the same time the researchers are providing a starting point for the development of tailor-made cancer therapies: "If we concentrate on a specific enzyme instead of a whole group, the therapies usually show much fewer side effects," says Kenner, describing the new therapeutic approach. The researchers were thus able to show that blocking one single target gene controlled by HDAC1, SNAIL1, is enough to reduce tumour growth by more than 80% in a short amount of time.

After the influence of HDAC1 on the immune response was recently proved by Christian Seiser and Univ. Prof. Mag. Dr. Wilfried Ellmeier, the latest findings could possibly represent another milestone in the study and treatment of malignant cancer cells.

» Original publication:
Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans
S. Lagger, D. Meunier, M. Mikula, R. Brunmeir, M. Schlederer, M. Artaker, O. Pusch, G. Egger, A. Hagelkruys, W. Mikulits, G. Weitzer, E. Muellner, M. Susani, L. Kenner and C. Seiser, The EMBO Journal (2010) doi:10.1038/emboj.2010.264