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Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia.
- Source :
-
Scientific reports [Sci Rep] 2020 Jun 25; Vol. 10 (1), pp. 10325. Date of Electronic Publication: 2020 Jun 25. - Publication Year :
- 2020
-
Abstract
- The FDA-approved DNA hypomethylating agents (DHAs) like 5-azacytidine (5AC) and decitabine (DAC) demonstrate efficacy in the treatment of hematologic malignancies. Despite previous reports that showed histone acetylation changes upon using these agents, the exact mechanism underpinning these changes is unknown. In this study, we investigated the relative potency of the nucleoside analogs and non-nucleoside analogs DHAs on DNA methylation reversal using DNA pyrosequencing. Additionally, we screened their effect on the enzymatic activity of the histone deacetylase sirtuin family (SIRT1, SIRT2, SIRT3, SIRT5 and SIRT6) using both recombinant enzymes and nuclear lysates from leukemia cells. The nucleoside analogs (DAC, 5AC and zebularine) were the most potent DHAs and increased the enzymatic activity of SIRT6 without showing any significant increase in other sirtuin isoforms. ChIP-Seq analysis of bone marrow cells derived from six acute myeloid leukemia (AML) patients and treated with the nucleoside analog DAC induced genome-wide acetylation changes in H3K9, the physiological substrate for SIRT6. Data pooling from the six patients showed significant acetylation changes in 187 gene loci at different chromosomal regions including promoters, coding exons, introns and distal intergenic regions. Signaling pathway analysis showed that H3K9 acetylation changes are linked to AML-relevant signaling pathways like EGF/EGFR and Wnt/Hedgehog/Notch. To our knowledge, this is the first report to identify the nucleoside analogs DHAs as activators of SIRT6. Our findings provide a rationale against the combination of the nucleoside analogs DHAs with SIRT6 inhibitors or chemotherapeutic agents in AML due to the role of SIRT6 in maintaining genome integrity and DNA repair.
- Subjects :
- Acetylation drug effects
Antimetabolites, Antineoplastic therapeutic use
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Azacitidine pharmacology
Azacitidine therapeutic use
Bone Marrow pathology
Cell Line, Tumor
Cytidine analogs & derivatives
Cytidine pharmacology
Cytidine therapeutic use
DNA Methylation drug effects
Decitabine pharmacology
Decitabine therapeutic use
Histones metabolism
Humans
Leukemia, Myeloid, Acute pathology
Antimetabolites, Antineoplastic pharmacology
Antineoplastic Combined Chemotherapy Protocols pharmacology
Leukemia, Myeloid, Acute drug therapy
Sirtuins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 32587297
- Full Text :
- https://doi.org/10.1038/s41598-020-67170-8