Abstract
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.
Highlights
As a common malignant cancer, esophageal cancer (EC)ranks sixth in the cause of cancer-related death all over the world[1]
All statistical tests were two-sided, and P < 0.05 was considered to indicate statistical significance. Increased expression of both OV6 and PRMT1 is significantly related with aberrant clinicopathological characteristics and poor prognosis in patients with Esophageal squamous cell carcinoma (ESCC)
The PRMT1 expression level was obviously upregulated in the ESCC cell lines compared with the HEEC normal esophageal epithelium cell line (Fig. 1c)
Summary
As a common malignant cancer, esophageal cancer (EC)ranks sixth in the cause of cancer-related death all over the world[1]. Esophageal squamous cell carcinoma (ESCC), the major histopathological type of esophageal cancer, is an aggressive tumour that is characterized by early. The significance of tumour initiating cells (TICs) was first identified in leukemia and soon reported in various solid tumours, such as breast, prostate and pancreatic cancers[4,5]. Official journal of the Cell Death Differentiation Association. Zhao et al Cell Death and Disease (2019)10:359 resistance. Studies reported that several cell surface markers in ESCC TICs have been identified, including CD133, CD44 and CD906–8. OV6, an epithelial origin marker, was initially verified in hepatocellular carcinoma TICs and associated with stem cell-like properties, including tumorigenicity, recurrence, chemoresistance and metastasis[9]. Our previous study identified OV6 as a novel esophageal TIC marker, because the OV6+
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