期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12960-6
关键词
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资金
- National Institutes of Health/National Cancer Institute [R01CA149623, R21CA155915, R03CA186176]
- Hormel Foundation
- Beijing Nova Program [2011114]
- National Natural Science Foundation of China [30800482, 30971297, 81102242, 81000221, 81270610, 81470010, 81170518, 81870117, 90919044]
- Beijing Natural Science Foundation of China [7102147, 7172200, 7132217]
- Hainan Provincial Natural Science Foundation of China [818MS157]
- Jilin Province Science and Technology Development Plan [20190201252JC]
- National Public Health Grand Research Foundation [201202017]
- National 973 Project of China [2005CB522400]
- [Z111107067311070]
The oncogenic fusion protein AML1-ETO retains the ability of AML1 to interact with the enhancer core DNA sequences, but blocks AML1-dependent transcription. Previous studies have shown that post-translational modification of AML1-ETO may play a role in its regulation. Here we report that AML1-ETO-positive patients, with high histone lysine methyltransferase Enhancer of zeste homolog 1 (EZH1) expression, show a worse overall survival than those with lower EZH1 expression. EZH1 knockdown impairs survival and proliferation of AML1-ETO-expressing cells in vitro and in vivo. We find that EZH1 WD domain binds to the AML1-ETO NHR1 domain and methylates AML1-ETO at lysine 43 (Lys43). This requires the EZH1 SET domain, which augments AML1-ETO-dependent repression of tumor suppressor genes. Loss of Lys43 methylation by point mutation or domain deletion impairs AML1-ETO-repressive activity. These findings highlight the role of EZH1 in non-histone lysine methylation, indicating that cooperation between AML1-ETO and EZH1 and AML1-ETO site-specific lysine methylation promote AML1-ETO transcriptional repression in leukemia.
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