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 dimethylat...

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Published inCell death and differentiation Vol. 27; no. 12; pp. 3226 - 3242
Main Authors Li, Zhongwei, Wang, Diandian, Lu, Jun, Huang, Baiqu, Wang, Yibo, Dong, Meichen, Fan, Dongmei, Li, Hongyuan, Gao, Yanyan, Hou, Pingfu, Li, Minle, Liu, Hui, Pan, Zhen-Qiang, Zheng, Junnian, Bai, Jin
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.12.2020
Nature Publishing Group
Subjects
13/1
13/105
13/51
13/89
14/19
38/22
38/90
42/109
631/208/200
631/67/1857
631/67/322
631/80/474/582
64/60
82/58
82/83
96/95
Apoptosis
Biochemistry
Biomedical and Life Sciences
Breast cancer
Breast carcinoma
Cell Biology
Cell Cycle Analysis
Gene expression
Histone methyltransferase
Life Sciences
Metastases
Metastasis
Molecular modelling
Phosphorylation
Stem Cells
TRAF6 protein
Ubiquitin
Ubiquitin-protein ligase
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Summary: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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ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-020-00615-9