Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia.
J Cancer Res Clin Oncol
; 144(6): 1065-1077, 2018 Jun.
Article
em En
| MEDLINE
| ID: mdl-29594337
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
/
Leucemia
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Benzazepinas
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Leucemia Mieloide Aguda
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Histona Desmetilases com o Domínio Jumonji
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Cancer Res Clin Oncol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China