Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia. Nat Commun 2019 Nov 07;10(1):5051
Date
11/09/2019Pubmed ID
31699991Pubmed Central ID
PMC6838331DOI
10.1038/s41467-019-12960-6Scopus ID
2-s2.0-85074693036 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
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.
Author List
Dou L, Yan F, Pang J, Zheng D, Li D, Gao L, Wang L, Xu Y, Shi J, Wang Q, Zhou L, Shen N, Singh P, Wang L, Li Y, Gao Y, Liu T, Chen C, Al-Kali A, Litzow MR, Chi YI, Bode AM, Liu C, Huang H, Liu D, Marcucci G, Liu S, Yu LAuthor
Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Line, Tumor
Cell Proliferation
Cell Survival
Core Binding Factor Alpha 2 Subunit
Gene Knockdown Techniques
Humans
Jurkat Cells
Leukemia, Myeloid, Acute
Methylation
Mice
Mice, Nude
Mutation
Neoplasm Transplantation
Oncogene Proteins, Fusion
Polycomb Repressive Complex 2
Prognosis
RNA, Messenger
RUNX1 Translocation Partner 1 Protein
THP-1 Cells
