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

Yunan Li, Mingying Zhang, Mengyao Sheng, Peng Zhang, Zizhen Chen, Wen Xing, Jie Bai, Tao Cheng, Feng-Chun Yang, Yuan Zhou

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalJournal of Cancer Research and Clinical Oncology
DOIs
StateAccepted/In press - Mar 28 2018

Fingerprint

Histone Demethylases
Acute Myeloid Leukemia
Myeloid Cells
Therapeutics
Histones
GSK-J4
Histone Code
RNA Sequence Analysis
Cell Line
Transcription Initiation Site
Cytarabine
Drug Delivery Systems
Cell Cycle Checkpoints
DNA Replication
Heterografts

Keywords

  • Acute myeloid leukemia
  • Histone demethylase
  • KDM6B
  • Small molecule inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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.

In: Journal of Cancer Research and Clinical Oncology, 28.03.2018, p. 1-13.

Research output: Contribution to journalArticle

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. In: Journal of Cancer Research and Clinical Oncology. 2018 ; pp. 1-13.
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AU - Li, Yunan

AU - Zhang, Mingying

AU - Sheng, Mengyao

AU - Zhang, Peng

AU - Chen, Zizhen

AU - Xing, Wen

AU - Bai, Jie

AU - Cheng, Tao

AU - Yang, Feng-Chun

AU - Zhou, Yuan

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N2 - 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.

AB - 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.

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KW - Small molecule inhibitor

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