Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors: predominant synergistic gene downregulation associated with gene body demethylation.
Biomarkers, Tumor
/ genetics
DNA Methylation
DNA Modification Methylases
/ antagonists & inhibitors
Decitabine
/ pharmacology
Demethylation
Down-Regulation
Drug Synergism
Enzyme Inhibitors
/ pharmacology
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Histone Deacetylase Inhibitors
/ pharmacology
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Panobinostat
/ pharmacology
Valproic Acid
/ pharmacology
TINAT
cancer-testis antigen (CTA)
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
15
06
2016
accepted:
06
09
2018
revised:
21
06
2018
pubmed:
25
11
2018
medline:
10
8
2019
entrez:
25
11
2018
Statut:
ppublish
Résumé
DNA methyltransferase inhibitors (DNMTi) approved for older AML patients are clinically tested in combination with histone deacetylase inhibitors (HDACi). The mechanism of action of these drugs is still under debate. In colon cancer cells, 5-aza-2'-deoxycytidine (DAC) can downregulate oncogenes and metabolic genes by reversing gene body DNA methylation, thus implicating gene body methylation as a novel drug target. We asked whether DAC-induced gene body demethylation in AML cells is also associated with gene repression, and whether the latter is enhanced by HDACi.Transcriptome analyses revealed that a combined treatment with DAC and the HDACi panobinostat or valproic acid affected significantly more transcripts than the sum of the genes regulated by either treatment alone, demonstrating a quantitative synergistic effect on genome-wide expression in U937 cells. This effect was particularly striking for downregulated genes. Integrative methylome and transcriptome analyses showed that a massive downregulation of genes, including oncogenes (e.g., MYC) and epigenetic modifiers (e.g., KDM2B, SUV39H1) often overexpressed in cancer, was associated predominantly with gene body DNA demethylation and changes in acH3K9/27. These findings have implications for the mechanism of action of combined epigenetic treatments, and for a better understanding of responses in trials where this approach is clinically tested.
Identifiants
pubmed: 30470836
doi: 10.1038/s41375-018-0293-8
pii: 10.1038/s41375-018-0293-8
doi:
Substances chimiques
Biomarkers, Tumor
0
Enzyme Inhibitors
0
Histone Deacetylase Inhibitors
0
Valproic Acid
614OI1Z5WI
Decitabine
776B62CQ27
Panobinostat
9647FM7Y3Z
DNA Modification Methylases
EC 2.1.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
945-956Références
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