Arginine methylation-dependent stabilization of SUV39H1 promotes breast cancer growth.

Suppressors of variegation 3-9 homolog 1 (SUV39H1), the enzyme responsible for establishing histone H3 lysine 9 trimethylation (H3K9me3) marks in heterochromatin, is frequently dysregulated in cancers. However, the mechanisms underlying SUV39H1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 1 (PRMT1) directly interacts with SUV39H1 and dimethylates it at arginine 378 (R378). PKC signaling-mediated phosphorylation of SUV39H1 at S391 enhances this interaction, thereby promoting its methylation. Notably, PRMT1 binds to SUV39H1 with higher affinity and binding free energy than MDM2, causing a structural clash that blocks MDM2-mediated ubiquitination of SUV39H1. Moreover, methylated SUV39H1 exhibits enhanced H3K9me3 methyltransferase activity and promotes tumor cell growth. A SUV39H1-derived peptide (TAT-SUV-peptide) disrupts the interaction between PRMT1 and SUV39H1, thereby reducing SUV39H1 methylation. Administration of TAT-SUV-peptide remarkably suppresses mammary tumor growth. Taken together, our findings reveal a critical phosphorylation-methylation-ubiquitination axis in controlling SUV39H1 stability and highlight its therapeutic potential through targeting SUV39H1 methylation.