Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia

Liping Dou, Fei Yan, Jiuxia Pang, Dehua Zheng, Dandan Li, Li Gao, Lijun Wang, Yihan Xu, Jinlong Shi, Qian Wang, Lei Zhou, Na Shen, Puja Singh, Lili Wang, Yonghui Li, Yvchi Gao, Tao Liu, Chongjian Chen, Aref Al-Kali, Mark R. Litzow, Young-In Chi, Ann M. Bode, Chunhui Liu, Haojie Huang, Daihong Liu, Guido Marcucci, Shujun Liu () and Li Yu ()
Additional contact information
Liping Dou: Medical School of Chinese PLA
Fei Yan: University of Minnesota
Jiuxia Pang: University of Minnesota
Dehua Zheng: Medical School of Chinese PLA
Dandan Li: Medical School of Chinese PLA
Li Gao: Medical School of Chinese PLA
Lijun Wang: University of Minnesota
Yihan Xu: Medical School of Chinese PLA
Jinlong Shi: Medical School of Chinese PLA
Qian Wang: Medical School of Chinese PLA
Lei Zhou: Medical School of Chinese PLA
Na Shen: University of Minnesota
Puja Singh: University of Minnesota
Lili Wang: Medical School of Chinese PLA
Yonghui Li: Medical School of Chinese PLA
Yvchi Gao: Annoroad Gene Technical Laboratory
Tao Liu: Annoroad Gene Technical Laboratory
Chongjian Chen: Annoroad Gene Technical Laboratory
Aref Al-Kali: Mayo Clinic
Mark R. Litzow: Mayo Clinic
Young-In Chi: University of Minnesota
Ann M. Bode: University of Minnesota
Chunhui Liu: Haoshi Biotechnical Laboratory
Haojie Huang: Mayo Clinic
Daihong Liu: Medical School of Chinese PLA
Guido Marcucci: City of Hope
Shujun Liu: University of Minnesota
Li Yu: Shenzhen University General Hospital, Shenzhen University Health Science Center

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12960-6

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