PRMT5-mediated arginine methylation of FXR1 is essential for RNA binding in cancer cells

Background: Our findings explain one of the molecular mechanisms of FXR1’s reported tumorigenic role in HNSCC and lay the groundwork for future research into how targeting the interface between FXR1 and PRMT5 can affect gene expression and aid in the development of novel therapies.

Results: Our previous findings demonstrated that overexpressed FXR1 in metastatic oral cancer cells (UMSCC-74A, -74B) and lung adenocarcinoma A549 cells contribute to tumor growth and proliferation (16,17). Silencing FXR1 promotes cellular senescence by activating CDKN1A (p21) and downregulating TERC RNA in both oral and lung A549 cells (16).

Discussion: The results of our study have revealed that FXR1 is a target of PRMT5 for arginine methylation. Furthermore, our data indicate that arginine methylation occurs explicitly in the NES and RGG box domains of FXR1 in cancer cells. Chromosome 3q amplification in lung and oral cancer patients leads to an increase in FXR1 mRNA levels and exert oncogenic properties. This study has identified and added a new feature that FXR1 protein undergoes post-translational modification by PRMT5-mediated arginine methylation, which enhances the stability of FXR1 protein. Our findings also show that PRMT5 directly adds a dimethyl group to FXR1 arginine residues in cancer cells. Therefore, further research is required to fully comprehend FXR1’s involvement in mRNA synthesis and turnover in cancer cells, leading to cancer growth and proliferation.

This work was supported by the National Institutes of Health NIH Grant R01 DE030013 and R21DE032461. Supported in part by the Translational Science Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313). This study received funding from the UNM Comprehensive Cancer Center assistance Grant NCI P30CA118100. The study also utilized the Analytical and Translational Genomics Shared Resource at University of New Mexico, which receives financial assistance from the State of New Mexico.