Epigenetic processes enable cells to respond to changes in their environment by regulating the activity of their genes. One of the proteins that plays a key role in gene activation is BRD4. To measure cellular BRD4 activity, the laboratory of Stefan Kubicek at the CeMM – Research Center for Molecular Medicine of the Austrian Academy of Sciences (OeAW) had generated a cellular reporter system in 2016.
Now the researchers were able to apply this model to systematically test whether loss of any of the approximately 23,000 human genes resembles BRD4 inhibition. Surprisingly, they discovered an interaction of folate metabolism with gene regulation. The results of the study, which among others included scientists from the Institute of Molecular Pathology (IMP) and the Medical University of Vienna, have now been published in the journal “Nature Genetics”.
New insights into gene regulation
"We had expected to find one of the classic epigenetic factors," said OeAW researcher Stefan Kubicek, "so we were all the more surprised that the best hit was MTHFD1." This enzyme is involved in folate metabolism, a process that had not previously been connected to BRD4. In addition, MTHFD1 is located predominantly in the cytoplasm, while BRD4 resides in the nucleus. However, subsequent experiments showed that the small portion of the MTHFD1 protein found in the nucleus interacts with BRD4. This interaction recruits MTHFD1 to the DNA, where the enzyme contributes to gene regulation.
The study is of clinical relevance for BRD4-dependent tumors. This includes tumors that harbor genetic aberrations leading to BRD4 overexpression, but also many other cancers in which BRD4 contributes to cell growth by its gene regulatory function. Accordingly, pharmaceutical companies have developed highly active BRD4 inhibitors, which are currently being tested in clinical trials. In clinical oncology, monotherapy with a single chemical agent is rarely successful due to the development of drug resistance.
New strategies for therapies
The discovery of the interaction of BRD4 and the enzyme MTHFD1 from the folic acid metabolism promises new approaches in cancer combination therapy, in the treatment of aggressive tumors. Antifolates, substances that inhibit the folate cycle, have been used for more than 70 years in cancer therapy and against diseases such as rheumatoid arthritis. The new study shows that antifolates can be combined with BRD4 inhibitors to more effectively combat tumors.
The results may also help to stratify patients to ensure therapy success. "In the best case, based on our findings, patients can also be selected who, because of their folic acid level and their genetics, respond particularly well to BRD4 inhibitors," says Stefan Kubicek.