A study published in Science Advances sheds new insights into the way cells introduce lactate modifications on histones and how these marks are removed again. The researchers hope this new development will improve understanding of the effect of medicine used to treat cancer.
Normal cells fuel themselves through a process called oxidative phosphorylation, whereby they use oxygen to turn food into energy. Because cancer cells need vast amounts of energy to grow and multiply quickly, they utilize a process known as glycolysis to consume and break down glucose. This phenomenon is called the “Warburg effect,” and it occurs in virtually all cancers, as well as other diseases.
An end product of the Warburg effect is lactic acid, or lactate, which was long considered a waste product. However, an emerging body of evidence suggests a non-metabolic role for lactate, but little is known about its exact epigenetic mechanisms.
In 2019, researchers from the University of Chicago found that histone proteins are modified by lactate on their lysine residues (lactyllysine), which provided a new connection between metabolism and epigenetics.
The latest research, led by Christian Adam Olsen, PhD, a professor at the Center for Biopharmaceuticals in the Department of Drug Design and Pharmacology at the University of Copenhagen, in collaboration with colleagues at the University of Chicago, further describes how lactic acid affects human cells. Their work shows how specific enzymes can remove lactic acid marks from proteins. These enzymes are members of the histone deacetylase (HDAC) enzyme class.
For the study, the research team grew healthy and cancerous human cell lines in the laboratory and marked different cell parts with fluorescence. Through these studies, they were able to observe the interactions between the enzymes and proteins in the cells. They noted that lactic acid levels increased when the enzymes were removed. They also saw that the same thing happened when drugs called HDAC inhibitors were used. Altogether, they were able to show that the enzymes were indeed able to remove lactic acid marks.
“Our new data provide insight into fundamental cellular epigenetic mechanisms that are affected by the activity of so-called histone deacetylase enzymes,” said Olsen. Histone modifications such as these are important because they can change whether a gene is “off” or “on.” This discovery may affect the development of new cancer medicine because the enzymes can be used as a target.
Olsen said one of the next steps that the group is interested in investigating is a third type of interaction with lactyllysine, mediated by what is referred to as reader domains. According to Olsen, the discovery of such recognition domains or proteins may uncover new targets for therapeutic intervention.
For now, the authors wrote that identifying these key regulatory enzymes will be a stepping stone for dissecting the functions of lactate signaling pathways in the future.
“It is our hope that many other laboratories around the world will find inspiration in our new study and explore new and innovative lines of research that we may not have considered ourselves,” he said.
