New potential target for colorectal cancer therapy

People with inflammatory bowel disease (IBD) also have an increased risk of developing colorectal cancer. However, the exact mechanisms behind this are still largely unknown. Researchers from the Cluster of Excellence “Precision Medicine in Chronic Inflammation” (PMI) and the DFG Research Unit “miTarget” are therefore trying to better understand this connection. A Kiel research team has now found that a protein that occurs unusually frequently in patients with IBD is also associated with colorectal cancer. If the responsible gene is removed from cancer cells, so that the protein can no longer be produced, tumor growth is inhibited. The researchers, led by PD Dr. Felix Sommer from the Institute of Clinical Molecular Biology (IKMB) of the Faculty of Medicine at Kiel University (CAU) and the University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, recently published their results in the journal Cancer Communications. The work was carried out in close cooperation within PMI with the research groups of Professor Philip Rosenstiel (IKMB), Professor Jan Rupp (UKSH Lübeck, Institute of Medical Microbiology), Professor Christoph Kaleta (Institute of Experimental Medicine, IEM), Professor Andreas Tholey (IEM) and Professor Christoph Röcken (UKSH Kiel, Institute of Pathology).

Protein HKDC1 influences tumor growth in the intestine

The protein HKDC1 (hexokinase domain containing 1) belongs to the hexokinase family along with four other similar enzymes. These are enzymes that play a particularly important role in carbohydrate metabolism in the body. Previous research had already shown that HKDC1 plays a role in some types of cancer. However, a role within colorectal cancer was not known. In addition, scientists from the PMI Cluster of Excellence, led by Professor Rosenstiel, had already shown that HKDC1 is upregulated in people with IBD. “In addition, we know that HKDC1 is mainly found in the intestine. We therefore wondered what it does there and whether it has an influence on the development of cancer in the gut,” reports one of the two first authors, PhD student Lea Järke from the group ‘Functional Host Microbiome Research’ at the IKMB.

PD Dr. Felix Sommer's team therefore conducted various experiments to investigate the effects of removing the gene responsible for producing the protein in colon cancer cells. If it is no longer present, the cell can no longer produce the protein. They carried out the experiments in cell culture, in organoids - artificial intestinal models in a petri dish - and in mouse models. “Among other things, we were able to observe that the cancer cells without HKDC1 no longer divide unhindered, they become more susceptible to external signals that lead to their death and, as a result, the tumors either do not develop at all or only to a greatly reduced extent,” reports the second first author, PhD student Saskia Weber-Stiehl, also from the ‘Functional Host Microbiome Research’ group at the IKMB. Further research must show whether the results may also be transferable to humans.

Blocking the enzyme could help IBD and colorectal cancer

The elevated production of HKDC1 in people with IBD could therefore explain why these patients are also more likely to develop colorectal cancer. The findings could be relevant for a possible therapy: both colon cancer and IBD could be influenced if HKDC1 is blocked - for example by chemical inhibitors or by targeted interventions in the microbiome. It is known that some cancer therapies are dependent on the microbiome. This is because the bacteria in the gut produce enzymes, for example, which can switch off active substances in cancer drugs or make them active in the first place. In addition, the researchers from Kiel have already shown for other members of the hexokinase family that these can be regulated by the microbiome. “In the case of HKDC1, it is also conceivable that the microbiome in the intestine influences the production of the enzyme. This is the subject of our current research,” says Sommer. “In the long term, we want to find out whether we can suppress hexokinase and thus tumor growth by modulating the microbiome,” Sommer continues.