Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia

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 thes...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Hetty E. Carraway, Sridhar A. Malkaram, Yana Cen, Aymen Shatnawi, Jun Fan, Hamdy E. A. Ali, Zakaria Y. Abd Elmageed, Thomm Buttolph, James Denvir, Donald A. Primerano, Tamer E. Fandy
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d954e9fb12024afa8636559b800189b6
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:d954e9fb12024afa8636559b800189b6
record_format	dspace
spelling	oai:doaj.org-article:d954e9fb12024afa8636559b800189b62021-12-02T17:45:12ZActivation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia10.1038/s41598-020-67170-82045-2322https://doaj.org/article/d954e9fb12024afa8636559b800189b62020-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-67170-8https://doaj.org/toc/2045-2322Abstract 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.Hetty E. CarrawaySridhar A. MalkaramYana CenAymen ShatnawiJun FanHamdy E. A. AliZakaria Y. Abd ElmageedThomm ButtolphJames DenvirDonald A. PrimeranoTamer E. FandyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hetty E. Carraway Sridhar A. Malkaram Yana Cen Aymen Shatnawi Jun Fan Hamdy E. A. Ali Zakaria Y. Abd Elmageed Thomm Buttolph James Denvir Donald A. Primerano Tamer E. Fandy Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia
description	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.
format	article
author	Hetty E. Carraway Sridhar A. Malkaram Yana Cen Aymen Shatnawi Jun Fan Hamdy E. A. Ali Zakaria Y. Abd Elmageed Thomm Buttolph James Denvir Donald A. Primerano Tamer E. Fandy
author_facet	Hetty E. Carraway Sridhar A. Malkaram Yana Cen Aymen Shatnawi Jun Fan Hamdy E. A. Ali Zakaria Y. Abd Elmageed Thomm Buttolph James Denvir Donald A. Primerano Tamer E. Fandy
author_sort	Hetty E. Carraway
title	Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia
title_short	Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia
title_full	Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia
title_fullStr	Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia
title_full_unstemmed	Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia
title_sort	activation of sirt6 by dna hypomethylating agents and clinical consequences on combination therapy in leukemia
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/d954e9fb12024afa8636559b800189b6
work_keys_str_mv	AT hettyecarraway activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia AT sridharamalkaram activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia AT yanacen activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia AT aymenshatnawi activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia AT junfan activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia AT hamdyeaali activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia AT zakariayabdelmageed activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia AT thommbuttolph activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia AT jamesdenvir activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia AT donaldaprimerano activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia AT tamerefandy activationofsirt6bydnahypomethylatingagentsandclinicalconsequencesoncombinationtherapyinleukemia
_version_	1718379616459030528

Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia

Ejemplares similares