Novel insight into PRMT5, a promising therapeutic target for cancer treatment
Despite progress in the treatment of patients with cancer, it is still a devastating disease with an urgent need for more precise and effective medicine. This requires a better understanding of the mechanism leading to cancer development, the definition of specific targets for the new medicine and insights into the role of these targets in cancer. Now, scientists at BRIC, University of Copenhagen and the Memorial Sloan Kettering Cancer Center, in collaboration with scientists from the University of Southern Denmark, have discovered why a promising new cancer drug target, PRMT5 is required for the proliferation of cancer cells.
PRMT5 regulates the splicing of our genes
PRMT5 is an enzyme that adds a chemical modification to proteins and regulates their function. Results from several laboratories have over the last few years demonstrated the requirement of PRMT5 for the proliferation of several types of cancer. This has led to the development of compounds that specifically can inhibit PRMT5 activity that are now in clinical trials. However, despite the strong clinical interest in targeted therapy aimed at PRMT5, it has not been clear why the protein is required for the proliferation of cancer cells. The new study from the research group of Professor Kristian Helin has provided important insights into the function of PRMT5.
“In this study, we aimed to identify proteins, which are modified by PRMT5 in leukemia. For this we used a technique called CRISPR interference, which allowed us to remove PRMT5 from cells and then investigate which proteins are no longer modified” says the first author on the study postdoc Aliaksandra Radzisheuskaya.
The results showed that PRMT5 modifies several important proteins. Of particular interest was the splicing regulator SRSF1, which is needed for RNA splicing. The splicing process is an essential and obligatory mechanism for the cell to live and divide, but without PRMT5 modifying SRSF1, the splicing process is not performed properly, which leads to cell death.
“In other words, we provide insight into why PRMT5 is required for the proliferation of cells and why it shows promise for targeted therapy,” says Aliaksandra Radzisheuskaya.
Improving cancer treatments through basic research
The first generation of PRMT5 inhibitors are currently in clinical trials, but in order to develop more efficient and specific drugs to target PRMT5, it is important to know how they affect normal and cancer cells. This knowledge is important for the development of cancer-specific treatments involving combination therapies and the development of second generation PRMT5 inhibitors with the hope of having a more specific and efficient treatment for cancer patients.
“In the future, we will further investigate, which of the identified PRMT5 targets or splicing changes could be used as biomarkers in predicting responses to PRMT5 inhibitors in the clinic”, says Kristian Helin, professor at BRIC and Chair of the Cell Biology Program at Memorial Sloan Kettering Cancer Center.
In addition, the research group will focus on investigating whether inhibition of PRMT5 can be efficiently combined with inhibitors of splicing or other pathways PRMT5 substrates are involved in.
Postdoc Aliaksandra Radzisheuskaya
Communication officer Emil Petersen