Hunting for new cancer drugs - Karl Ekwall

The fact that the histones have proved significant to the activation and deactivation of genes has increased interest in histone research. Associate Professor Karl Ekwall and his research group at the Department of Natural Sciences, Södertörn University College are researching into how histones can be changed or modified and how this affects active genes.

"Our research is purely basic research, but there are major opportunities for medical applications," says Ekwall.

DNA twisted into histones forms a complex called chromatin. When histones are changed or modified, the structure of the chromatin is changed It may be said that the chromatin becomes more or less "open" depending on how tightly wound the DNA is and this is important to which of the chromosome's genes are switched on at that time. When a gene is active, the protein is produced for which the gene comprises the pattern.

"The structure of chromatin can control not only whether a gene is on or off, but also give different degrees of activation and also affect how quickly it can take place," explains Ekwall.

The histones in the chromatin can be modified biochemically by various enzymes in conjunction with small, short RNA chains (RNA = ribonucleic acid). So these histone-modified enzymes are important to the regulation of the gene's expression. Karl Ekwall and his co-workers are studying such enzymes with the aid of yeast cells as a model organism. The yeast fungi being used are known as fission yeast.

"This model system works very well since the histone-modified processes seem to have been essentially preserved during evolution. This means that there are major similarities between the processes in yeast cells and human cells."

One of the enzymes, to which the group is devoting a lot of research work goes by the abbreviation of HDAC.

"This enzyme is interesting not least because it has proved to be important in various diseases, chiefly cancer," says Ekwall.

An abnormal amount of HDAC is produced in a number of tumorous diseases. Producing drugs to combat HDAC's effect on the cells (known as HDAC inhibitors) is an interesting trail in treatment research in the field of cancer. Some such drug candidates are under development and have reached the stage where they are being tested on trial volunteers.

"Continued research into the different HDAC variants and the histone-modifying processes to which the enzyme contributes will hopefully lead to further candidates for new tumour drugs."

Ekwall's research group is also working on studies of another structure in the cell nucleus, namely the centromeres found at the centre of the chromosomes. The centromere plays a vital role in cell division by ensuring that the chromosomes are allocated in the right way between the daughter cells when the parent cell divides: Errors in this function in germ cells taking part in conception can lead to chromosomal disorders in the child, such as Downs Syndrome. Small RNA molecules and histone-modified enzymes are also important to the function of centromeres, meaning that there are many links between the group's two research trails.

epigenetic process

Epigenetics is the science of conditions and processes in the chromosomes which do not affect the content of genetic material, but which conversely do affect how this content is expressed. Epigenetic patterns are normally hereditary. An example of an epigenetic process is histone modifications.

From 2004-2009, the EU is supporting a research network aimed at epigenetic research, called "The Epigenome Network of Excellence". Karl Ekwall and his research group are involved in this European network, which aims to develop epigenetic research through such things as increased collaboration.