SHMT2 arginine methylation by PRMT1 facilitates esophageal cancer progression by enhancing glycolysis and one-carbon metabolism

Abstract

Abstract Background Protein arginine methyltransferase 1 (PRMT1) is the main enzyme that directly responsible for the production of asymmetric dimethylarginine (ADMA), and upregulation of PRMT1 is observed in a variety of malignancies, including esophageal cancer (ESCA). Dysregulation of arginine methylation caused by PRMT1 overexpression is a driver of poor cancer progression, and the detailed mechanism of modulation is currently unknown. Results The present study confirmed a novel oncogenic mechanism of PRMT1 in ESCA. PRMT1 levels were significantly upregulated in ESCA, and its high expression correlated with TNM stage and poor patient prognosis. We continued to find the mechanisms by which PRMT1 expression was more relevant to ESCA progression. RNA-seq and KEGG enrichment analyses revealed that differentially expressed genes after PRMT1 silencing in ESCA might modulate serine/one-carbon metabolism. Knockdown of PRMT1 in vitro resulted in a significant reduction in ESCA cell growth, and indicators related to serine/one-carbon metabolism and glycolysis, whereas its overexpression showed opposite results. The catalytic activity of PRMT1 was crucial in mediating these biological processes. We found that PRMT1 mediated the ADMA modification of serine hydroxymethyltransferase 2 (SHMT2) at arginine 415 (R415), which activated SHMT2 activity and enhanced serine/one-carbon metabolism and glycolysis. The R415K mutation largely eliminated the arginine methylation of SHMT2 by PRMT1, and weakened PRMT1-induced glycolysis and serine/one-carbon metabolism. Conclusion Our study further confirmed the link between the two proteins, PRMT1 and SHMT2, as well as arginine methylation and glycolysis. The study of deeper molecular mechanisms will reveal a broader role of arginine methylation in the regulation of glycolysis.