PRMT1 regulates the tumour-initiating properties of esophageal squamous cell carcinoma through histone H4 arginine methylation coupled with transcriptional activation

Esophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to a paucity of effective targeted therapy. ESCC is believed to arise from tumour initiating cells (TICs), which contribute to metastasis and chemoresistance. In this study, we found that Protein arginine methyltransferase 1(PRMT1) was highly expressed in ESCCs and associated with aberrant clinicopathological characteristics of ESCC patients. In ESCC specimens, the elevated expression of PRMT1 and OV6 was significantly associated with histologic grade, TNM stage and poor patient prognosis. Moreover, overexpression of PRMT1 was observed in esophageal TICs purified by magnetic sorting of adherent and spheroid ECA109/TE1 cells. The increased level of PRMT1 in TICs facilitated the expression of TIC markers, stem cell-like properties, resistance to chemotherapy, tumorigenicity and increased their percentages in ECSS samples. Conversely, knockdown of PRMT1 significantly diminished the self-renewal properties of ESCC. Moreover, we show that PRMT1 can catalyse histone H4R3 asymmetric dimethylation and promote transcription activation of down-stream genes. Further RNA-Seq transcriptome analysis reveals that overexpression of PRMT1 in ESCC cell lines activates Wnt/β-catenin and Notch signaling pathway. Together, our studies highlight that PRMT1 activates and maintains esophageal TICs by mediating transcription alteration through histone H4 arginine methylation.