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Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia

PURPOSE: Acute myeloid leukemia (AML) is a heterogeneous disease with poor outcomes. Despite increased evidence shows that dysregulation of histone modification contributes to AML, specific drugs targeting key histone modulators are not applied in the clinical treatment of AML. Here, we investigated...

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Autores principales: Li, Yunan, Zhang, Mingying, Sheng, Mengyao, Zhang, Peng, Chen, Zizhen, Xing, Wen, Bai, Jie, Cheng, Tao, Yang, Feng-Chun, Zhou, Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948279/
https://www.ncbi.nlm.nih.gov/pubmed/29594337
http://dx.doi.org/10.1007/s00432-018-2631-7
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author Li, Yunan
Zhang, Mingying
Sheng, Mengyao
Zhang, Peng
Chen, Zizhen
Xing, Wen
Bai, Jie
Cheng, Tao
Yang, Feng-Chun
Zhou, Yuan
author_facet Li, Yunan
Zhang, Mingying
Sheng, Mengyao
Zhang, Peng
Chen, Zizhen
Xing, Wen
Bai, Jie
Cheng, Tao
Yang, Feng-Chun
Zhou, Yuan
author_sort Li, Yunan
collection PubMed
description PURPOSE: Acute myeloid leukemia (AML) is a heterogeneous disease with poor outcomes. Despite increased evidence shows that dysregulation of histone modification contributes to AML, specific drugs targeting key histone modulators are not applied in the clinical treatment of AML. Here, we investigated whether targeting KDM6B, the demethylase of tri-methylated histone H3 lysine 27 (H3K27me3), has a therapeutic potential for AML. METHODS: A KDM6B-specific inhibitor, GSK-J4, was applied to treat the primary cells from AML patients and AML cell lines in vitro and in vivo. RNA-sequencing was performed to reveal the underlying mechanisms of inhibiting KDM6B for the treatment of AML. RESULTS: Here we observed that the mRNA expression of KDM6B was up-regulated in AML and positively correlated with poor survival. Treatment with GSK-J4 increased the global level of H3K27me3 and reduced the proliferation and colony-forming ability of primary AML cells and AML cell lines. GSK-J4 treatment significantly induced cell apoptosis and cell-cycle arrest in Kasumi-1 cells, and displayed a synergistic effect with cytosine arabinoside. Notably, injection of GSK-J4 attenuated the disease progression in a human AML xenograft mouse model in vivo. Treatment with GSK-J4 predominantly resulted in down-regulation of DNA replication and cell-cycle-related pathways, as well as abrogated the expression of critical cancer-promoting HOX genes. ChIP-qPCR validated an increased enrichment of H3K27me3 in the transcription start sites of these HOX genes. CONCLUSIONS: In summary, our findings suggest that targeting KDM6B with GSK-J4 has a therapeutic potential for the treatment of AML. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00432-018-2631-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-59482792018-05-17 Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia Li, Yunan Zhang, Mingying Sheng, Mengyao Zhang, Peng Chen, Zizhen Xing, Wen Bai, Jie Cheng, Tao Yang, Feng-Chun Zhou, Yuan J Cancer Res Clin Oncol Original Article – Cancer Research PURPOSE: Acute myeloid leukemia (AML) is a heterogeneous disease with poor outcomes. Despite increased evidence shows that dysregulation of histone modification contributes to AML, specific drugs targeting key histone modulators are not applied in the clinical treatment of AML. Here, we investigated whether targeting KDM6B, the demethylase of tri-methylated histone H3 lysine 27 (H3K27me3), has a therapeutic potential for AML. METHODS: A KDM6B-specific inhibitor, GSK-J4, was applied to treat the primary cells from AML patients and AML cell lines in vitro and in vivo. RNA-sequencing was performed to reveal the underlying mechanisms of inhibiting KDM6B for the treatment of AML. RESULTS: Here we observed that the mRNA expression of KDM6B was up-regulated in AML and positively correlated with poor survival. Treatment with GSK-J4 increased the global level of H3K27me3 and reduced the proliferation and colony-forming ability of primary AML cells and AML cell lines. GSK-J4 treatment significantly induced cell apoptosis and cell-cycle arrest in Kasumi-1 cells, and displayed a synergistic effect with cytosine arabinoside. Notably, injection of GSK-J4 attenuated the disease progression in a human AML xenograft mouse model in vivo. Treatment with GSK-J4 predominantly resulted in down-regulation of DNA replication and cell-cycle-related pathways, as well as abrogated the expression of critical cancer-promoting HOX genes. ChIP-qPCR validated an increased enrichment of H3K27me3 in the transcription start sites of these HOX genes. CONCLUSIONS: In summary, our findings suggest that targeting KDM6B with GSK-J4 has a therapeutic potential for the treatment of AML. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00432-018-2631-7) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2018-03-28 2018 /pmc/articles/PMC5948279/ /pubmed/29594337 http://dx.doi.org/10.1007/s00432-018-2631-7 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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.
spellingShingle Original Article – Cancer Research
Li, Yunan
Zhang, Mingying
Sheng, Mengyao
Zhang, Peng
Chen, Zizhen
Xing, Wen
Bai, Jie
Cheng, Tao
Yang, Feng-Chun
Zhou, Yuan
Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia
title Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia
title_full Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia
title_fullStr Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia
title_full_unstemmed Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia
title_short Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia
title_sort therapeutic potential of gsk-j4, a histone demethylase kdm6b/jmjd3 inhibitor, for acute myeloid leukemia
topic Original Article – Cancer Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948279/
https://www.ncbi.nlm.nih.gov/pubmed/29594337
http://dx.doi.org/10.1007/s00432-018-2631-7
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