Discovery of novel CARM1 targets is hoped to facilitate the development of new therapeutics for breast cancer


Using a quantitative mass spectrometry approach, researchers at the University of Wisconsin – Madison have globally profiled the protein targets of CARM1 in breast cancer. CARM1, a methyltransferase, has long been implicated in breast cancer.  The finding may facilitate the development of CARM1-specific inhibitors for breast cancer management.

CARM1 (coactivator-associated arginine methyltransferase 1) belongs to a family of enzymes known as PRMTs (protein arginine methyltransferases), which can introduce arginine methylation. CARM1 is also referred to as PRMT4. Protein methylation, the addition of a methyl group to target proteins, is one type of post-translational modification that can change the function of the target proteins.

CARM1 has been reported to be overexpressed in breast cancer, and its overexpression is associated with high-grade tumors and poorer prognosis. So CARM1-specific inhibitors are considered a promising breast cancer therapy. However, until now only a few targets of CARM1 have been identified, and how it recognizes these targets remains unclear.

Prof. Wei Xu, who led the new study, previously found two targets of CARM1: BAF155 and MED12. Additionally, CARM1-mediated BAF155 methylation correlates with breast cancer progression and metastasis.

In this work, Xu's team employed multiple techniques including high-resolution mass spectrometry to globally profile CARM1 targets in two human breast cancer cell lines. They identified more than 300 CARM1-dependent arginine methylation events, and verified about 130 new CARM1 protein targets, many of which have cancer-related functions. Further, they also found that the N-terminus of CARM1 is necessary for target recognition and methylation. The researchers hypothesized that the design of CARM1-specific inhibitors should focus on the N-terminus of CARM1.

In conclusion, the study extends our knowledge of CARM1, provides insights into the working mechanism of other PRMTs, and opens up an avenue of drug discovery for breast cancer. Since CARM1 is also overexpressed in many other cancer types, the findings, which are described in Nature Communications, could have broad implications.
 
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