Nat Genet: epigenetic study reveals a new combination therapy for aggressive cancer

June 4, 2019 / BIOON / - epigenetic process enables cells to respond to changes in the environment by regulating the activity of cell genes One of the proteins that play a key role in gene activation is Brd4, which is a well-studied epigenetic reader that binds to acetyl lysine residues on histones and non histones In order to measure Brd4 activity of cells, Stefan Kubicek Laboratory of CeMM research center of molecular medicine, Austrian Academy of Sciences generated a cell reporting system in 2016 Now, researchers use this model to test whether any deletion of about 23000 human genes has a similar effect to Brd4 inhibition Surprisingly, they found an interaction between folate metabolism and gene regulation The study involved scientists from the Institute of molecular pathology (IMP) and the Vienna Medical University, and the results have been published in the journal Nature Genetics Photo source: Modern genome-wide screening technology of Nature Genetics makes it possible to produce mutant cell populations, and one gene in each cell is destroyed Brd4 reporting cells enable Stefan Kubicek to select precisely those cells that exhibit Brd4 inhibition from these cell populations in CeMM's laboratory Next generation sequencing is then used to determine which genes are turned off Kubicek said: "we thought we could find a classic epigenetic factor, so we were even more surprised that the most suitable gene was mthfd1 "This enzyme is involved in folate metabolism, which has never been found to be related to Brd4 before In addition, mthfd1 is mainly located in the cytoplasm, while Brd4 is located in the nucleus These coincidences provide another piece of puzzle for the first author Sara sdelci, confirming the research results At a meeting, she met Philip rathert from the imp Johannes Zuber lab, who is also working on Brd4 Sara sdelci said: "data from Philipp rathert show that mthfd1 is also physically integrated with Brd4 "In subsequent experiments, she found that a small part of the mthfd1 protein found in the nucleus interacted with Brd4 This interaction absorbs mthfd1 into DNA, where the enzyme is involved in gene regulation The study of Sara sdelci has clinical significance for Brd4 dependent tumors This includes tumors that carry genes that cause Brd4 overexpression, as well as many other cancers in which Brd4 promotes cell growth through its gene regulatory function Therefore, pharmaceutical companies have developed Brd4 inhibitors with high activity, which are currently being tested in clinical trials In clinical oncology, due to the development of drug resistance, single drug treatment of single chemical agent is rarely successful The discovery of the interaction between Brd4 and mthfd1 in folate metabolism provides a new way for the combined treatment of tumor and the treatment of aggressive tumor Anti folate is a kind of substance which can inhibit folate circulation It has been used in cancer treatment and rheumatoid arthritis for more than 70 years New research shows that anti folate can be used in combination with Brd4 inhibitors to fight tumor more effectively The results also help to classify patients to ensure treatment success Stefan Kubicek said: "according to our research results, in the best case, we can also select patients who respond particularly well to Brd4 inhibitors according to their folate levels and genes "Reference: Sara sdelci et al, mthfd1 interaction with Brd4 links folder metadata to transactional regulation, Nature Genetics (2019) Doi: 10.1038/s41588-019-0413-z