Histone Deacetylase Inhibitors (HDI) Cause DNA Damage in Leukemia Cells: A Mechanism for Leukemia-Specific HDI-Dependent Apoptosis?

Abstract

Histone deacetylase inhibitors (HDI) increase gene expression through induction of histone acetylation. However, it remains unclear whether increases in specific gene expression events determine the apoptotic response following HDI administration. Herein, we show that a variety of HDI trigger in hematopoietic cells not only widespread histone acetylation and DNA damage responses but also actual DNA damage, which is significantly increased in leukemic cells compared with normal cells. Thus, increase in H2AX and ataxia telangiectasia mutated (ATM) phosphorylation, early markers of DNA damage, occurs rapidly following HDI administration. Activation of the DNA damage and repair response following HDI treatment is further emphasized by localizing DNA repair proteins to regions of DNA damage. These events are followed by subsequent apoptosis of neoplastic cells but not normal cells. Our data indicate that induction of apoptosis by HDI may result predominantly through accumulation of excessive DNA damage in leukemia cells, leading to activation of

Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

“…Moreover, acetylation of histones induced by HDAC inhibitors can induce an open chromatin structure more accessible not only to transcription complexes but also to therapeutic agents that affect DNA. HDAC inhibitors are also able to induce DNA damage by themselves by changing chromatin structure and activation of ataxia telangiectasia mutated kinase and histone H2A.X (15). Consistent with these reports, we identified DNA damage in sensitive H526, H146, H82, and DMS114 cells from 5-AZA-dC or MGCD0103 alone.…”

“…Reduction of cell viability by both 5-AZA-dC and HDAC inhibitors could also result from their genotoxic effects (10,15,37,41,42). 5-AZA-dC is incorporated into DNA and covalently binds with DNMTs with the 5-AZA-DNMT-DNA adducts causing DNA damage (43).…”

“…Acetylation of histones affects the transcription of genes by modification of chromatin structure and is dependent on the contrasting actions of histone acetyltransferase and HDAC (13). Like DNMT inhibitors, HDAC inhibitors exhibit their antineoplastic effects by enhancing differentiation, apoptosis, growth inhibition, cell cycle arrest, and cell death through DNA damage by transcriptional modulation of antiapoptotic and proapoptotic genes (14)(15)(16)(17)(18).…”

“…The mechanism underlying HDAC inhibitor-induced DNA damage is still not entirely understood. Possibly, it occurs through changes in chromatin structure and is associated with the acetylation of histone proteins (15). Moreover, HDAC inhibitors may suppress the removal of the incorporated 5-AZA-dC from DNA and significantly increase DNA damage induced by 5-AZA-dC (10).…”

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

“…Numerous mechanisms have been proposed to account for HDACI-mediated lethality, including oxidative damage, up-regulation of death receptors or proapoptotic proteins (e.g. Bim), down-regulation of anti-apoptotic proteins, and more recently, DNA damage induction and/or interference with DNA repair proteins (3,5,6).HDACIs also increase acetylation of various non-histone proteins including chaperone proteins (7), DNA repair proteins (e.g. Ku70) (8), and transcription factors, e.g.…”