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Methylation of EZH2 by PRMT1 regulates its stability and promotes breast cancer metastasis


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.

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Fig. 1: PRMT1 interacts with and dimethylates EZH2 at arginine 342.
Fig. 2: PRMT1 elevates the expression of EZH2 protein.
Fig. 3: PRMT1-mediated meR342-EZH2 inhibits CDK1-mediated EZH2 phosphorylation.
Fig. 4: PRMT1-mediated meR342-EZH2 prevents TRAF6-mediated EZH2 ubiquitination and degradation.
Fig. 5: PRMT1-mediated meR342-EZH2 promotes its ability in silencing target gene transcriptional expression.
Fig. 6: EZH2-R342 methylation promotes breast cancer cell invasion and metastasis.
Fig. 7: EZH2-R342 methylation positive correlates with metastasis and poor prognosis of breast cancer patients.


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This work was supported by the grants from the National Natural Science Foundation of China (81802637, 81672845 and 81872304); the Natural Science Foundation of Jiangsu Province (BK20180989); the National Postdoctoral Research Funds (2019M651971); the Natural Science Foundation of Jiangsu Province Universities (18KJB310016); the Research Foundation of Xuzhou Medical University (D2018020); the Xuzhou City Science and Technology Plan Project (KC19065); the Jiangsu Provincial Key Medical Discipline, the Project of Invigorating Health Care through Science, Technology and Education (ZDXKA2016014).

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Correspondence to Junnian Zheng or Jin Bai.

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Li, Z., Wang, D., Lu, J. et al. Methylation of EZH2 by PRMT1 regulates its stability and promotes breast cancer metastasis. Cell Death Differ 27, 3226–3242 (2020).

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