PRMT1 介导的 EZH2 甲基化调控其稳定性并促进乳腺癌转移。
Methylation of EZH2 by PRMT1 regulates its stability and promotes breast cancer metastasis.
机构信息
Cancer Institute, Xuzhou Medical University, Xuzhou, China.
Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
出版信息
Cell Death Differ. 2020 Dec;27(12):3226-3242. doi: 10.1038/s41418-020-00615-9. Epub 2020 Sep 7.
Enhancer of zeste homolog 2 (EZH2), a key histone methyltransferase and EMT inducer, is overexpressed in diverse carcinomas, including breast cancer. However, the molecular mechanisms of EZH2 dysregulation in cancers are still largely unknown. Here, we discover that EZH2 is asymmetrically dimethylated at R342 (meR342-EZH2) by PRMT1. meR342-EZH2 was found to inhibit the CDK1-mediated phosphorylation of EZH2 at T345 and T487, thereby attenuating EZH2 ubiquitylation mediated by the E3 ligase TRAF6. We also demonstrate that meR342-EZH2 resulted in a decrease in EZH2 target gene expression, but an increase in breast cancer cell EMT, invasion and metastasis. Moreover, we confirm the positive correlations among PRMT1, meR342-EZH2 and EZH2 expression in the breast cancer tissues. Finally, we report that high expression levels of meR342-EZH2 predict a poor clinical outcome in breast cancer patients. Our findings may provide a novel diagnostic target and promising therapeutic target for breast cancer metastasis.
增强子结合蛋白 2（EZH2）是一种关键的组蛋白甲基转移酶和 EMT 诱导剂，在多种癌症中过度表达，包括乳腺癌。然而，EZH2 在癌症中的失调的分子机制在很大程度上仍然未知。在这里，我们发现 PRMT1 使 EZH2 在 R342 处发生不对称二甲基化（meR342-EZH2）。发现 meR342-EZH2 抑制 CDK1 介导的 EZH2 在 T345 和 T487 处的磷酸化，从而减弱 EZH2 由 E3 连接酶 TRAF6 介导的泛素化。我们还证明，meR342-EZH2 导致 EZH2 靶基因表达减少，但乳腺癌细胞 EMT、侵袭和转移增加。此外，我们在乳腺癌组织中证实了 PRMT1、meR342-EZH2 和 EZH2 表达之间的正相关。最后，我们报告说 meR342-EZH2 的高表达水平预示着乳腺癌患者的临床预后不良。我们的研究结果可能为乳腺癌转移提供了一个新的诊断靶点和有前途的治疗靶点。
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