NDLI: Histone deacetylase 1 induced by neddylation inhibition contributes to drug resistance in acute myelogenous leukemia

Content Provider	Springer Nature : BioMed Central
Author	Lai, Qiu-yu He, Ying-zhi Peng, Xiong-wen Zhou, Xuan Liang, Dan Wang, Liang
Abstract	Objective This study aimed to investigate the function and mechanism of neddylation of HDAC1 underlying drug resistance of AML cells. Methods Evaluation experiments of effects of HDAC1 on drug resistance of AML cells were performed with AML cell transfected with constructs overexpressing HDAC1 or multi-drug resistance AML cells transfected with siRNA for HDAC1 through observing cell viability, percentage of apoptotic cell, doxorubicin-releasing index and multidrug resistance associated protein 1 (MRP1) expression. Neddylation or ubiquitination of HDAC1 was determined by immunoprecipitation or Ni2+ pull down assay followed by western blot. The role of HDAC1 was in vivo confirmed by xenograft in mice. Results HDAC1 was significantly upregulated in refractory AML patients, and in drug-resistant AML cells (HL-60/ADM and K562/A02). Intracellular HDAC1 expression promoted doxorubicin resistance of HL-60, K562, and primary bone marrow cells (BMCs) of remission AML patients as shown by increasing cell viability and doxorubicin-releasing index, inhibiting cell apoptosis. Moreover, HDAC1 protein level in AML cells was regulated by the Nedd8-mediated neddylation and ubiquitination, which further promoted HDAC1 degradation. In vivo, HDAC1 overexpression significantly increased doxorubicin resistance; while HDACs inhibitor Panobinostat markedly improved the inhibitory effect of doxorubicin on tumor growth. Furthermore, HDAC1 silencing by Panobinostat and/or lentivirus mediated RNA interference against HDAC1 effectively reduced doxorubicin resistance, resulting in the inhibition of tumor growth in AML bearing mice. Conclusion Our findings suggested that HDAC1 contributed to the multidrug resistance of AML and its function turnover was regulated, at least in part, by post-translational modifications, including neddylation and ubiquitination.
Related Links	https://biosignaling.biomedcentral.com/counter/pdf/10.1186/s12964-019-0393-8.pdf
Ending Page	14
Page Count	14
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s12964-019-0393-8
Journal	Cell Communication and Signaling
Issue Number	1
Volume Number	17
Language	English
Publisher	BioMed Central
Publisher Date	2019-07-29
Access Restriction	Open
Subject Keyword	Cell Biology Protein-Ligand Interactions Receptors Cytokines and Growth Factors Acute myelogenous leukemia Drug resistance HDAC1 Neddylation Ubiquitination
Content Type	Text
Resource Type	Article
Subject	Biochemistry Cell Biology Molecular Biology
Journal Impact Factor	8.2/2023
5-Year Journal Impact Factor	8/2023

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