title: HDAC Inhibition Induces MicroRNA-182, which Targets RAD51 and Impairs HR Repair to Sensitize Cells to Sapacitabine in Acute Myelogenous Leukemia.
abstract: 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.
authors: Division of Hematology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors: Tsung-Huei
authors: TH
authors: Lai
authors: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors: Brett
authors: B
authors: Ewald
authors: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors: Alma
authors: A
authors: Zecevic
authors: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors: Chaomei
authors: C
authors: Liu
authors: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors: Melanie
authors: M
authors: Sulda
authors: Division of Hematology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors: Dimitrios
authors: D
authors: Papaioannou
authors: Division of Hematology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors: Ramiro
authors: R
authors: Garzon
authors: Division of Hematology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors: James S
authors: JS
authors: Blachly
authors: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. deepa.sampath@osumc.edu wplunket@mdanderson.org.
authors: William
authors: W
authors: Plunkett
authors: Division of Hematology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. deepa.sampath@osumc.edu wplunket@mdanderson.org.
authors: Deepa
authors: D
authors: Sampath
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001087:Arabinonucleosides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics*; D059767:Recombinational DNA Repair / Q000187:drug effects*
chemical_list: D001087:Arabinonucleosides; D056572:Histone Deacetylase Inhibitors; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D003596:Cytosine; D051135:Rad51 Recombinase; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; C117959:sapacitabine