Journal Article

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

Xu, Yihan, Chi, Young-In, Yan, Fei, Litzow, Mark R., Gao, Yvchi, Liu, Chunhui, Wang, Lijun, Gao, Li, Liu, Shujun, Pang, Jiuxia, Al-Kali, Aref, Li, Yonghui, Zheng, Dehua, Chen, Chongjian, Shen, Na, Singh, Puja, Marcucci, Guido, Shi, Jinlong, Dou, Liping, Yu, Li, Liu, Daihong, Bode, Ann M., Wang, Lili, Zhou, Lei, Wang, Qian, Liu, Tao, Huang, Haojie, Li, Dandan

2019

Overview

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. The oncogenic fusion protein AML1-ETO has the ability of AML1 to interact with DNA but blocks AML1-dependent transcription. Here the authors report that histone lysine methyltransferase EZH1 interacts with AML1-ETO and methylates AML1-ETO at lysine 43, promoting AML1-ETO transcriptional repression in leukemia.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 38 / 38/1 / 38/109 / 38/15 / 38/23 / 38/39 / 38/91 / 631/337 / 631/337/458/1648 / 631/337/572 / 631/67/1990/283/1897 / 692/699/67/1990/283 / 82/83 / AML1 protein / Animals / Cell Line, Tumor / Cell proliferation / Cell Proliferation - genetics / Cell Survival - genetics / Clonal deletion / Core Binding Factor Alpha 2 Subunit - genetics / Core Binding Factor Alpha 2 Subunit - metabolism / Deoxyribonucleic acid / DNA / DNA methylation / Fusion protein / Gene deletion / Gene Knockdown Techniques / Gene sequencing / Gene silencing / Histones / Homology / Humanities and Social Sciences / Humans / Jurkat Cells / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - metabolism / Lysine / Methylation / Methyltransferase / Mice / Mice, Nude / multidisciplinary / Mutation / Neoplasm Transplantation / Nucleotide sequence / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Point mutation / Polycomb Repressive Complex 2 - genetics / Polycomb Repressive Complex 2 - metabolism / Post-translation / Prognosis / Proteins / RNA, Messenger - metabolism / RUNX1 Translocation Partner 1 Protein - genetics / RUNX1 Translocation Partner 1 Protein - metabolism / Science / Science (multidisciplinary) / Survival / THP-1 Cells / Tumor suppressor genes