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Bookmarks in the human book of life

Histone acetyltransferases (HATs) and their antagonists, the histone deacetylases (HDACs), are important enzymes in epigenetic gene regulation. They control the chemical conversion of nuclear proteins, the histones, which are the major protein components of chromatin.

Histone acetyltransferases (HAT) add an acetyl group to histones in the vicinity of certain genes, which can then be removed by histone deacetylases (HDACs). These acetyl groups are rather like bookmarks that show transcription factors where to access the DNA, allowing gene transcription to occur. They also serve as a stop signal for the transcription of genes. Faulty acetylation can lead to malignant cells, a process which can however be reversed by HAT or HDAC inhibitors. The pharmaceutical chemists Manfred Jung from Freiburg and Wolfgang Sippl from Halle discovered new HAT inhibitors that are now being investigated for their potential as anti-cancer drugs. The research project is funded by the Wilhelm Sander Foundation.

HAT inhibitors are potential anti-cancer drugs

The human genome project resulted in the deciphering of the entire human genome. The genetic code harbours the construction plans for all cellular components. This is often referred to as the book of life and it contains all necessary information for constructing organisms. However, knowledge of the genetic code is insufficient because there are additional modificatory processes that determine which chapters of the book are read. For example, caterpillars and butterflies or human muscle and skin cells have the same genetic code but use epigenetic information to extend and modulate the genetic code. Epigenetics thus refers to the concept that certain factors can cause an organism’s genes to behave differently, even though the genes do not change. Faults in the epigenetic code can turn healthy cells into cancer cells.
Detection of acetylation using immunofluorescence (yellow, left and right); DNA staining (blue, left) (Photo: M. Hendzel, Cross Cancer Institute Edmonton)
Detection of acetylation using immunofluorescence (yellow, left and right); DNA staining (blue, right) (Photo: M. Hendzel, Cross Cancer Institute Edmonton)
HAT and HDAC inhibitors can correct misdirected epigenetic processes and thus prevent the uncontrolled proliferation of cells. Numerous HDAC inhibitors are known and the first HDAC inhibitor is already available in the USA as a drug for the treatment of T-cell lymphoma. However, HAT inhibitors that might be suitable for the therapy of cancer are still unknown.

Computer-assisted screening supports drug discovery

The research project of Wolfgang Sippl and Manfred Jung focuses on the computer-assisted screening of potential HAT inhibitors and the synthesis of new active substances that will then be tested in the test tube for their ability to block HAT. Subsequently, the inhibitors will be tested for their inhibitory effect on the growth of cancer cells in culture dishes and suitable candidates identified and further characterised.

The work is being carried out in close cooperation with Dr. I. Fichtner from the Max Delbrück Centre for Molecular Medicine and Prof. Dr. M. Hendzel from the Cross Cancer Institute in Edmonton, Canada. The researchers are also focusing on the visualisation of what happens when histones are modified. The modification of cancer cell histones can be made visible under the fluorescence microscope using dye-labelled antibodies against acetyl groups. This helps the researchers to find new selective and potent HAT inhibitors in order to evaluate their therapeutic potential. Many more years of research will certainly be needed before the inhibitors can be used for the treatment of cancer patients. 

Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/bookmarks-in-the-human-book-of-life