Arginine Methyltransferase PRMT5 Methylates and Destabilizes Mxi1 to Confer Radioresistance in Lung Cancer

BackgroundRadioresistance is regarded as the main cause of local recurrence and distant metastasis in lung cancer. However, the underlying mechanisms of radioresistance remain incompletely understood. This study investigates the roles and regulatory mechanisms of arginine methyltransferase PRMT5 in lung cancer radioresistance.MethodsImmunoprecipitation assay and GST pulldown were used to detect the protein-protein interaction. The methylation of Mxi1 was determined by in vivo and in vitro arginine methylation assays. In vivo ubiquitination and CHX chase assays were performed to examine the stability of Mxi1. The biological effects of PRMT5 and its specific inhibitor EPZ015666 in lung cancer were evaluated both in vitro and in vivo.ResultsWe show that the arginine methyltransferase PRMT5 interacts with and methylates Mxi1, which promotes the binding of the β-Trcp ligase to Mxi1, facilitating the ubiquitination and degradation of Mxi1 in lung cancer. Furthermore, genetic blockade of PRMT5 impairs DNA damage repair and enhances lung cancer radiosensitivity in vitro and in vivo, and these phenotypes are partially reversed by Mxi1 silencing. More importantly, pharmacological inhibition of PRMT5 with the specific inhibitor EPZ015666 leads to extraordinary radiosensitization in vitro and in vivo in lung cancer.ConclusionsOur data indicate that PRMT5 methylates and destabilizes Mxi1 to confer radioresistance, suggesting that PRMT5 may be a promising radiosensitization target in lung cancer.