Abstract
Although the involvement of protein arginine methyltransferase 1 (PRMT1) in tumorigenesis has been reported, its roles in breast cancer progression and metastasis has not been elucidated. Here we identified PRMT1 as a key regulator of the epithelial-mesenchymal transition (EMT) in breast cancer. We showed that the EMT program induced by PRMT1 endowed the human mammary epithelial cells with cancer stem cell properties. Moreover, PRMT1 promoted the migratory and invasive behaviors in breast cancer cells. We also demonstrated that abrogation of PRMT1 expression in breast cancer cells abated metastasis in vivo in mouse model. In addition, knockdown of PRMT1 arrested cell growth in G1 tetraploidy and induced cellular senescence. Mechanistically, PRMT1 impacted EMT process and cellular senescence by mediating the asymmetric dimethylation of arginine 3 of histone H4 (H4R3me2as) at the ZEB1 promoter to activate its transcription, indicating the essential roles of this epigenetic control both in EMT and in senescence. Thus, we unraveled a dual function of PRMT1 in modulation of both EMT and senescence via regulating ZEB1. This finding points to the potent value of PRMT1 as a dual therapeutic target for preventing metastasis and for inhibiting cancer cell growth in malignant breast cancer patients.
Highlights
We explored whether PRMT1 can trigger epithelial-to-mesenchymal transition (EMT) in breast cancer cells
We found that the MCF10A-PRMT1 cells displayed a dramatic change in cell morphology, characterized by the transformation from the cobblestone-like epithelial cells with tight cell-tocell adhesion, into a spindle-shaped fibroblast-like morphology with distinct cellular scattering (Fig. 1c)
The PRMT1v1 and v2 mRNA expression was elevated in both breast cancer cell lines and in breast tumour tissues compared to their normal controls, and a strong correlation between PRMT1v1 and poor patient prognosis was established[25,37]
Summary
High expression of PRMT1 has shown to be indicative of the disease progression and aggressiveness in breast and colon cancer[25,26]. H4R3me2as was found to be positively correlated with increasing tumour grade in prostate cancer[27] These findings indicate that both PRMT1 and H4R3me2as may probably contribute to tumour malignancy and aggressiveness. Knockdown of PRMT1 suppressed metastasis in vivo in mice, and provoked cellular senescence in breast cancer cells. These functional effects of PRMT1 were exerted through the control of ZEB1 transcriptional expression via H4R3me2as modification at gene’s promoter. We have identified a novel role and regulatory mechanism of PRMT1 in breast cancer cell proliferation and metastasis, which may provide clues for the development of new epigenetic intervention targeting PRMT1 for advanced breast cancers
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