J Korean Med Sci.
2013 Feb;28(2):237-246. 10.3346/jkms.2013.28.2.237.
Improved Therapeutic Effect against Leukemia by a Combination of the Histone Methyltransferase Inhibitor Chaetocin and the Histone Deacetylase Inhibitor Trichostatin A
- Affiliations
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- 1Genome Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Hwasun, Korea. hjoonk@chonnam.ac.kr
- 2Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
- 3Department of Preventive Medicine, College of Medicine, Seonam University, Namwon, Korea.
- 4Environmental Health Center for Childhood Leukemia and Cancer, Chonnam National University Hwasun Hospital, Hwasun, Korea.
- KMID: 1429188
- DOI: http://doi.org/10.3346/jkms.2013.28.2.237
Abstract
- SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.
MeSH Terms
-
Acetylation/drug effects
Adolescent
Adult
Aged
Apoptosis/*drug effects
Cadherins/metabolism
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p15/metabolism
DNA Methylation/drug effects
Enzyme Inhibitors/therapeutic use/*toxicity
Frizzled Receptors/metabolism
Gene Expression Regulation/drug effects
HL-60 Cells
Histone Deacetylase Inhibitors/therapeutic use/*toxicity
Histone-Lysine N-Methyltransferase/*antagonists & inhibitors/metabolism
Histones/genetics/metabolism
Humans
Hydroxamic Acids/therapeutic use/*toxicity
K562 Cells
Leukemia/drug therapy/metabolism/pathology
Leukemia, Myeloid, Acute/genetics/metabolism/pathology
Male
Middle Aged
Piperazines/therapeutic use/toxicity
Promoter Regions, Genetic
Young Adult
Cadherins
Cyclin-Dependent Kinase Inhibitor p15
Enzyme Inhibitors
Frizzled Receptors
Histone Deacetylase Inhibitors
Histones
Hydroxamic Acids
Piperazines
Histone-Lysine N-Methyltransferase
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