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Molecular targets for therapy

Targeting HDAC3, a new partner protein of AKT in the reversal of chemoresistance in acute myeloid leukemia via DNA damage response

Leukemia volume 31, pages 2761–2770 (2017)Cite this article

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Abstract

Resistance to cytotoxic chemotherapy drugs remains as the major cause of treatment failure in acute myeloid leukemia. Histone deacetylases (HDAC) are important regulators to maintain chromatin structure and control DNA damage; nevertheless, how each HDAC regulates genome stability remains unclear, especially under genome stress conditions. Here, we identified a mechanism by which HDAC3 regulates DNA damage repair and mediates resistance to chemotherapy drugs. In addition to inducing DNA damage, chemotherapy drugs trigger upregulation of HDAC3 expression in leukemia cells. Using genetic and pharmacological approaches, we show that HDAC3 contributes to chemotherapy resistance by regulating the activation of AKT, a well-documented factor in drug resistance development. HDAC3 binds to AKT and deacetylates it at the site Lys20, thereby promoting the phosphorylation of AKT. Chemotherapy drug exposure enhances the interaction between HDAC3 and AKT, resulting in decrease in AKT acetylation and increase in AKT phosphorylation. Whereas HDAC3 depletion or inhibition abrogates these responses and meanwhile sensitizes leukemia cells to chemotoxicity-induced apoptosis. Importantly, in vivo HDAC3 suppression reduces leukemia progression and sensitizes MLL-AF9+ leukemia to chemotherapy. Our findings suggest that combination therapy with HDAC3 inhibitor and genotoxic agents may constitute a successful strategy for overcoming chemotherapy resistance.

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Acknowledgements

We thank all fellows from Research Center for Experimental Medicine for their technical assistance. In addition, we thank all researchers from Shanghai Institute of Hematology for kind advice and the supply of research reagents. This Study is supported by the Ministry of Science and Technology of China (S2016G9074) and National Natural Science Foundation of China (81270615, 81270621, 81123005).

Author contributions

JL, WYF and LC performed the experiments, analyzed the data and helped to write the manuscript; WHG performed experiments and helped with animal experiments; YS and MYJ helped with animal experiments; YXZ helped to collect primary samples; YW, HBD and WJZ provided advice and revised the paper; JZ provided material and advice, and revised the paper; ABL, JML and JH designed the overall concept, analyzed the data and wrote the paper.

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Author notes

  1. J Long, W Y Fang and L Chang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    J Long, W Y Fang, L Chang, W H Gao, M Y Jia, Y X Zhang, Y Wang, H B Dou, J Zhu, J M Li & Jiong Hu

  2. Tissue Bank Biotechnology, Shanghai International Medical Zone, Shanghai, China

    J Long

  3. Shanghai Xuhui District Central Hospital, Zhongshan-Xuhui Hospital, Shanghai, China

    L Chang

  4. Research Center for Experimental Medicine, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Y Shen

  5. Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China

    W J Zhang & A B Liang

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Long, J., Fang, W., Chang, L. et al. Targeting HDAC3, a new partner protein of AKT in the reversal of chemoresistance in acute myeloid leukemia via DNA damage response. Leukemia 31, 2761–2770 (2017). https://doi.org/10.1038/leu.2017.130

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