Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Cell Death Dis. 2021 Nov 13;12(11):1080. doi: 10.1038/s41419-021-04381-5.
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.
蛋白质精氨酸甲基转移酶 1（PRMT1）能够促进乳腺癌细胞增殖。然而，PRMT1 介导的乳腺癌细胞增殖的详细机制在很大程度上尚不清楚。在本研究中，我们揭示了 PRMT1 介导的 EZH2 在 R342 位的甲基化（meR342-EZH2）对 PRMT1 诱导的细胞增殖有很大影响。我们还证明了 meR342-EZH2 可以在体外和体内加速乳腺癌细胞的增殖。此外，我们表明 meR342-EZH2 通过抑制 P16 和 P21 转录表达来促进细胞周期进程。就机制而言，我们说明 meR342-EZH2 通过防止 AMPKα1 介导的 pT311-EZH2 磷酸化，促进 EZH2 与 SUZ12 的结合和 PRC2 组装，从而抑制 P16 和 P21 转录，增强 EZH2 表达，并增加 P16 和 P21 启动子处的 H3K27me3 富集。最后，我们验证了 PRMT1 和 meR342-EZH2 的表达与 pT311-EZH2 的表达呈负相关。我们的研究结果表明，meR342-EZH2 可能成为治疗乳腺癌的新的治疗靶点。
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