HDAC Inhibition Induces MicroRNA-182, which Targets RAD51 and Impairs HR Repair to Sensitize Cells to Sapacitabine in Acute Myelogenous Leukemia

The double-strand breaks elicited by sapacitabine, a clinically active nucleoside analogue prodrug, are repaired by RAD51 and the homologous recombination repair (HR) pathway, which could potentially limit its toxicity. We investigated the mechanism by which histone deacetylase (HDAC) inhibitors tar...

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Veröffentlicht in:Clinical cancer research 2016-07, Vol.22 (14), p.3537-3549
Hauptverfasser: Lai, Tsung-Huei, Ewald, Brett, Zecevic, Alma, Liu, Chaomei, Sulda, Melanie, Papaioannou, Dimitrios, Garzon, Ramiro, Blachly, James S, Plunkett, William, Sampath, Deepa
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container_end_page 3549
container_issue 14
container_start_page 3537
container_title Clinical cancer research
container_volume 22
creator Lai, Tsung-Huei
Ewald, Brett
Zecevic, Alma
Liu, Chaomei
Sulda, Melanie
Papaioannou, Dimitrios
Garzon, Ramiro
Blachly, James S
Plunkett, William
Sampath, Deepa
description The double-strand breaks elicited by sapacitabine, a clinically active nucleoside analogue prodrug, are repaired by RAD51 and the homologous recombination repair (HR) pathway, which could potentially limit its toxicity. We investigated the mechanism by which histone deacetylase (HDAC) inhibitors targeted RAD51 and HR to sensitize acute myelogenous leukemia (AML) cells to sapacitabine. Chromatin immunoprecipitation identified the role of HDACs in silencing miR-182 in AML. Immunoblotting, gene expression, overexpression, or inhibition of miR-182 and luciferase assays established that miR-182 directly targeted RAD51. HR reporter assays, apoptotic assays, and colony-forming assays established that the miR-182, as well as the HDAC inhibition-mediated decreases in RAD51 inhibited HR repair and sensitized cells to sapacitabine. The gene repressors, HDAC1 and HDAC2, became recruited to the promoter of miR-182 to silence its expression in AML. HDAC inhibition induced miR-182 in AML cell lines and primary AML blasts. miR-182 targeted RAD51 protein both in luciferase assays and in AML cells. Overexpression of miR-182, as well as HDAC inhibition-mediated induction of miR-182 were linked to time- and dose-dependent decreases in the levels of RAD51, an inhibition of HR, increased levels of residual damage, and decreased survival after exposure to double-strand damage-inducing agents. Our findings define the mechanism by which HDAC inhibition induces miR-182 to target RAD51 and highlights a novel pharmacologic strategy that compromises the ability of AML cells to conduct HR, thereby sensitizing AML cells to DNA-damaging agents that activate HR as a repair and potential resistance mechanism. Clin Cancer Res; 22(14); 3537-49. ©2016 AACR.
doi_str_mv 10.1158/1078-0432.CCR-15-1063
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We investigated the mechanism by which histone deacetylase (HDAC) inhibitors targeted RAD51 and HR to sensitize acute myelogenous leukemia (AML) cells to sapacitabine. Chromatin immunoprecipitation identified the role of HDACs in silencing miR-182 in AML. Immunoblotting, gene expression, overexpression, or inhibition of miR-182 and luciferase assays established that miR-182 directly targeted RAD51. HR reporter assays, apoptotic assays, and colony-forming assays established that the miR-182, as well as the HDAC inhibition-mediated decreases in RAD51 inhibited HR repair and sensitized cells to sapacitabine. The gene repressors, HDAC1 and HDAC2, became recruited to the promoter of miR-182 to silence its expression in AML. HDAC inhibition induced miR-182 in AML cell lines and primary AML blasts. miR-182 targeted RAD51 protein both in luciferase assays and in AML cells. 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We investigated the mechanism by which histone deacetylase (HDAC) inhibitors targeted RAD51 and HR to sensitize acute myelogenous leukemia (AML) cells to sapacitabine. Chromatin immunoprecipitation identified the role of HDACs in silencing miR-182 in AML. Immunoblotting, gene expression, overexpression, or inhibition of miR-182 and luciferase assays established that miR-182 directly targeted RAD51. HR reporter assays, apoptotic assays, and colony-forming assays established that the miR-182, as well as the HDAC inhibition-mediated decreases in RAD51 inhibited HR repair and sensitized cells to sapacitabine. The gene repressors, HDAC1 and HDAC2, became recruited to the promoter of miR-182 to silence its expression in AML. HDAC inhibition induced miR-182 in AML cell lines and primary AML blasts. miR-182 targeted RAD51 protein both in luciferase assays and in AML cells. 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subjects Apoptosis - drug effects
Apoptosis - genetics
Arabinonucleosides - pharmacology
Cell Line, Tumor
Cytosine - analogs & derivatives
Cytosine - pharmacology
DNA Damage - drug effects
DNA Damage - genetics
Gene Expression - drug effects
Gene Expression - genetics
HeLa Cells
Histone Deacetylase 1 - antagonists & inhibitors
Histone Deacetylase 2 - antagonists & inhibitors
Histone Deacetylase Inhibitors - pharmacology
Histone Deacetylases - metabolism
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - metabolism
MicroRNAs - genetics
Promoter Regions, Genetic - drug effects
Promoter Regions, Genetic - genetics
Rad51 Recombinase - genetics
Recombinational DNA Repair - drug effects
title HDAC Inhibition Induces MicroRNA-182, which Targets RAD51 and Impairs HR Repair to Sensitize Cells to Sapacitabine in Acute Myelogenous Leukemia
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