Methylation of C/EBPa by PRMT1 Inhibits Its Tumor-Suppressive Function in Breast Cancer

C/EBPa is an essential transcription factor involved in regulating the expression or function of certain cell-cycle regulators, including in breast cancer cells. Although protein arginine methyltransferases have been shown to play oncogenic roles in a variety of cancers, little is known about the role of arginine methylation in regulating the antiproliferation activity of C/EBPa. Here, we report that the protein arginine methyltransferase 1 (PRMT1) is overexpressed in human breast cancer and that elevated PRMT1 correlates with cancer malignancy. RNA-sequencing analysis revealed that knockdown of PRMT1 in breast cancer cells is accompanied by a decrease in the expression of pro-proliferative genes, including cyclin D1. Furthermore, tandem affinity purification followed by mass spectrometry identified PRMT1 as a component of the C/EBPa complex. C/EBPa associated with and was methylated by PRMT1 at three arginine residues (R35, R156, and R165). PRMT1-dependent methylation of C/EBPa promoted the expression of cyclin D1 by blocking the interaction between C/EBPa and its corepressor HDAC3, which resulted in rapid growth of tumor cells during the pathogenesis of breast cancer. Inhibition of PRMT1 significantly impeded the growth of cancer cells from patients with triple-negative breast cancer. This evidence that PRMT1 mediates C/EBPa methylation sheds light on a novel pathway and potential therapeutic target in breast cancer. Significance: This study provides novel mechanistic insight of the role of the arginine methyltransferase PRMT1 in breast cancer pathogenesis.