Abstract
Protein arginine methyltransferase 1 (PRMT1) is able to promote breast cancer cell proliferation. However, the detailed mechanisms of PRMT1-mediated breast cancer cell proliferation are largely unknown. In this study, we reveal that PRMT1-mediated methylation of EZH2 at the R342 site (meR342-EZH2) has a great effect on PRMT1-induced cell proliferation. We also demonstrate that meR342-EZH2 can accelerate breast cancer cell proliferation in vitro and in vivo. Further, we show that meR342-EZH2 promotes cell cycle progression by repressing P16 and P21 transcription expression. In terms of mechanism, we illustrate that meR342-EZH2 facilitates EZH2 binding with SUZ12 and PRC2 assembly by preventing AMPKα1-mediated phosphorylation of pT311-EZH2, which results in suppression of P16 and P21 transcription by enhancing EZH2 expression and H3K27me3 enrichment at P16 and P21 promoters. Finally, we validate that the expression of PRMT1 and meR342-EZH2 is negatively correlated with pT311-EZH2 expression. Our findings suggest that meR342-EZH2 may become a novel therapeutic target for the treatment of breast cancer.
Highlights
Protein arginine methyltransferase 1 (PRMT1), a member of the PRMT family, is able to catalyse many substrates, promoting arginine methylation [1]
We discovered that meR342-Enhancer of zeste homologue 2 (EZH2) is positively correlated with PRMT1 expression in breast cancer tissues, whereas meR342-EZH2 is negatively correlated with pT311-EZH2 expression in breast cancer tissues
PRMT1 promotes cell proliferation by mediating meR342EZH2 in breast cancer In our previous study, we found that PRMT1 catalyses EZH2-R342 asymmetric dimethylarginines (ADMAs) generation
Summary
Protein arginine methyltransferase 1 (PRMT1), a member of the PRMT family, is able to catalyse many substrates (including histone and non-histone proteins), promoting arginine methylation [1]. Many reports have demonstrated that the ectopic expression of PRMT1 in a variety of cancers plays a key role in cancer tumorigenesis and metastasis [3,4,5,6,7,8,9,10]. Our previous study showed that overexpression of PRMT1 inhibits breast cancer cell senescence by increasing ZEB1 expression [11]. EZH2 is a critical histone methyltransferase that is able to suppress PRC2 target gene transcription by mediating the trimethylation of Lys-27 in histone H3 (H3K27me3) [14, 15]. Many reports have demonstrated that EZH2 is ectopically expressed in cancer cells [16,17,18]. A previous study found that SOX4 promotes breast cancer metastasis by increasing EZH2 transcription [17]. An increasing number of reports have demonstrated that a variety of EZH2 target genes are tumour suppressors, such as HOXA7, HOXA9, DAB2IP, P16 and P21 [18, 21,22,23,24,25]
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