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 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.

DCTPP1, an Oncogene Regulated by miR-378a-3p, Promotes Proliferation of Breast Cancer via DNA Repair Signaling Pathway

“…DNA repair pathways are DNA damage response mechanisms ( 28 , 29 ). DNA repair pathways influence cell survival and are anti-cancer therapeutic targets of radiotherapy and cytotoxic chemotherapy ( 30 , 31 ). γh2A is a major agent in DNA damage or repair ( 32 ).…”

The Chromatin Remodeling Protein BRG1 Regulates SREBP Maturation by Activating SCAP Transcription in Hepatocytes

“…There are a few indications wherein the SCAP promoter appears to be influenced by epigenetic modifications. Carraway et al (2020) have shown that histone H3K9 acetylation and DNA methylation can differentially regulate SCAP expression in leukemia cells although the involvement of specific histone/DNA modifying enzymes is not clear at this point. It would be of great interest to further examine the epigenetic mechanism whereby SCAP transcription is regulated to provide more flexibility in targeting the SREBP pathway.…”

Integrative Analysis of Multi-Omics Identified the Prognostic Biomarkers in Acute Myelogenous Leukemia

“…DNA methylation plays an important role in the regulation of the occurrence and development of AML ( 26 ). Some scholars have added DNA methylation inhibitors to refractory AML patients and found that the vast majority of AML patients can significantly prolong the survival time ( 24 ). Besides, the methylated GGH promoter associates with the variability of methotrexate responses in AML patients ( 27 ).…”

“…Besides DNA methylation being strongly associated with prognosis of AML patients, it has been reported that different methylation types have different clinical outcomes for AML patients ( 23 ). And DNA methylated genes can be used as therapeutic targets in AML ( 24 ).…”