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

被引：18

作者：

Dou, Liping ^{[1
,2
]}

Yan, Fei ^{[2
,3
]}

Pang, Jiuxia ^{[2
]}

Zheng, Dehua ^{[4
]}

Li, Dandan ^{[1
]}

Gao, Li ^{[1
]}

Wang, Lijun ^{[2
]}

Xu, Yihan ^{[1
]}

Shi, Jinlong ^{[1
]}

Wang, Qian ^{[1
]}

Zhou, Lei ^{[1
]}

Shen, Na ^{[2
]}

Singh, Puja ^{[2
]}

Wang, Lili ^{[1
]}

Li, Yonghui ^{[1
]}

Gao, Yvchi ^{[5
]}

Liu, Tao ^{[5
]}

Chen, Chongjian ^{[5
]}

Al-Kali, Aref ^{[6
]}

Litzow, Mark R. ^{[6
]}

Chi, Young-In ^{[2
]}

Bode, Ann M. ^{[2
]}

Liu, Chunhui ^{[7
]}

Huang, Haojie ^{[8
]}

Liu, Daihong ^{[1
]}

Marcucci, Guido ^{[9
]}

Liu, Shujun ^{[2
]}

Yu, Li ^{[10
]}

机构：

[1] Chinese Peoples Liberat Army Gen Hosp, Med Sch Chinese PLA, Dept Hematol, 28 Fuxing Rd, Beijing 100853, Peoples R China

[2] Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA

[3] Jilin Univ, Int Joint Res Lab Nanomicro Architecture Chem NMA, State Key Lab Inorgan Synth & Preparat Chem, Int Res Ctr Chem Med Joint Innovat,Coll Chem, 2699 Qianjin St, Changchun 130012, Jilin, Peoples R China

[4] Chinese Peoples Liberat Army Gen Hosp, Med Sch Chinese PLA, Dept Hepatol, 28 Fuxing Rd, Beijing 100853, Peoples R China

[5] Annord Gene Tech Lab, 6 Kechuang Rd, Beijing 100176, Peoples R China

[6] Mayo Clin, Div Hematol, 200 1st St SW, Rochester, MN 55905 USA

[7] Haoshi Biotech Lab, 1 Pingshan First Rd, Shenzhen 518055, Peoples R China

[8] Mayo Clin, Dept Biochem & Mol Biol, 200 1st St SW, Rochester, MN 55905 USA

[9] City Hope Natl Med Ctr, Dept Hematol Malignancies Translat Sci, 1500 East Duarte Rd, Duarte, CA 91010 USA

[10] Shenzhen Univ, Hlth Sci Ctr, Int Canc Ctr, Dept Hematol Oncol,Gen Hosp, 1098 Xueyuan Ave, Shenzhen 518060, Peoples R China

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

美国国家卫生研究院; 北京市自然科学基金; 海南省自然科学基金; 中国国家自然科学基金;

关键词：

ACUTE MYELOID-LEUKEMIA; GENE-EXPRESSION; CHROMATIN; COMPLEX; PRC2; LEUKEMOGENESIS; ACETYLATION;

D O I：

10.1038/s41467-019-12960-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：15

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