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Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia
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-po...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838331/ https://www.ncbi.nlm.nih.gov/pubmed/31699991 http://dx.doi.org/10.1038/s41467-019-12960-6 |
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author | Dou, Liping Yan, Fei Pang, Jiuxia Zheng, Dehua Li, Dandan Gao, Li Wang, Lijun Xu, Yihan Shi, Jinlong Wang, Qian Zhou, Lei Shen, Na Singh, Puja Wang, Lili Li, Yonghui Gao, Yvchi Liu, Tao Chen, Chongjian Al-Kali, Aref Litzow, Mark R. Chi, Young-In Bode, Ann M. Liu, Chunhui Huang, Haojie Liu, Daihong Marcucci, Guido Liu, Shujun Yu, Li |
author_facet | Dou, Liping Yan, Fei Pang, Jiuxia Zheng, Dehua Li, Dandan Gao, Li Wang, Lijun Xu, Yihan Shi, Jinlong Wang, Qian Zhou, Lei Shen, Na Singh, Puja Wang, Lili Li, Yonghui Gao, Yvchi Liu, Tao Chen, Chongjian Al-Kali, Aref Litzow, Mark R. Chi, Young-In Bode, Ann M. Liu, Chunhui Huang, Haojie Liu, Daihong Marcucci, Guido Liu, Shujun Yu, Li |
author_sort | Dou, Liping |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6838331 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68383312019-11-12 Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia Dou, Liping Yan, Fei Pang, Jiuxia Zheng, Dehua Li, Dandan Gao, Li Wang, Lijun Xu, Yihan Shi, Jinlong Wang, Qian Zhou, Lei Shen, Na Singh, Puja Wang, Lili Li, Yonghui Gao, Yvchi Liu, Tao Chen, Chongjian Al-Kali, Aref Litzow, Mark R. Chi, Young-In Bode, Ann M. Liu, Chunhui Huang, Haojie Liu, Daihong Marcucci, Guido Liu, Shujun Yu, Li Nat Commun Article 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. Nature Publishing Group UK 2019-11-07 /pmc/articles/PMC6838331/ /pubmed/31699991 http://dx.doi.org/10.1038/s41467-019-12960-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Dou, Liping Yan, Fei Pang, Jiuxia Zheng, Dehua Li, Dandan Gao, Li Wang, Lijun Xu, Yihan Shi, Jinlong Wang, Qian Zhou, Lei Shen, Na Singh, Puja Wang, Lili Li, Yonghui Gao, Yvchi Liu, Tao Chen, Chongjian Al-Kali, Aref Litzow, Mark R. Chi, Young-In Bode, Ann M. Liu, Chunhui Huang, Haojie Liu, Daihong Marcucci, Guido Liu, Shujun Yu, Li Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia |
title | Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia |
title_full | Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia |
title_fullStr | Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia |
title_full_unstemmed | Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia |
title_short | Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia |
title_sort | protein lysine 43 methylation by ezh1 promotes aml1-eto transcriptional repression in leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838331/ https://www.ncbi.nlm.nih.gov/pubmed/31699991 http://dx.doi.org/10.1038/s41467-019-12960-6 |
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