Purpose The double strand breaks elicited by sapacitabine, a clinically active nucleoside analog prodrug are repaired by Rad51 and the homologous recombination repair (HR) pathway which could potentially limit its toxicity. We investigated the mechanism by which HDAC inhibitors targeted Rad51 and HR to sensitize AML cells to sapacitabine. Experimental Design Chromatin immunoprecipitation identified the role of HDACs in silencing microRNA-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. Results 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. Conclusions Our findings define the mechanism by which HDAC inhibition induces miR-182 to target Rad51 and highlights a novel pharmacological 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.