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

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.

SUBMITTER: Lai QY

PROVIDER: S-EPMC6664585 | biostudies-other | 2019 Jul

REPOSITORIES: biostudies-other

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

Lai Qiu-Yu QY He Ying-Zhi YZ Peng Xiong-Wen XW Zhou Xuan X Liang Dan D Wang Liang L

Cell communication and signaling : CCS 20190729 1

<h4>Objective</h4>This study aimed to investigate the function and mechanism of neddylation of HDAC1 underlying drug resistance of AML cells.<h4>Methods</h4>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 assoc ...[more]

PMID: 31358016

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Project description:Histone deacetylase inhibitors (HDACIs) activate the prosurvival nuclear factor-?B (NF-?B) pathway by hyperacetylating RelA/p65, whereas the chemopreventive agent resveratrol inhibits NF-?B by activating the class III histone deacetylase Sirt1. Interactions between resveratrol and pan-HDACIs (vorinostat and panobinostat) were examined in human acute myelogenous leukemia (AML) cells. Pharmacologically achievable resveratrol concentrations (25-50 ?M) synergistically potentiated HDACI lethality in AML cell lines and primary AML blasts. Resveratrol antagonized RelA acetylation and NF-?B activation in HDACI-treated cells. However, short hairpin RNA Sirt1 knockdown failed to modify HDACI sensitivity, which suggests that factors other than or in addition to Sirt1 activation contribute to resveratrol/HDACI interactions. These interactions were associated with death receptor 5 (DR5) up-regulation and caspase-8 activation, whereas cells expressing dominant-negative caspase-8 were substantially protected from resveratrol/HDACI treatment, which suggests a significant functional role for the extrinsic apoptotic pathway in lethality. Exposure to resveratrol with HDACI induced sustained reactive oxygen species (ROS) generation, which was accompanied by increased levels of DNA double-strand breaks, as reflected in ?H2A.X and comet assays. The free radical scavenger Mn(III)tetrakis(4-benzoic acid)porphyrin chloride blocked ROS generation, DR5 up-regulation, caspase-8 activation, DNA damage, and apoptosis, which indicates a primary role for oxidative injury in lethality. Analyses of cell-cycle progression and 5-ethynyl-2'-deoxyuridine incorporation through flow cytometry revealed that resveratrol induced S-phase accumulation; this effect was abrogated by HDACI coadministration, which suggests that cells undergoing DNA synthesis may be particularly vulnerable to HDACI lethality. Collectively, these findings indicate that resveratrol interacts synergistically with HDACIs in AML cells through multiple ROS-dependent actions, including death receptor up-regulation, extrinsic apoptotic pathway activation, and DNA damage induction. They also raise the possibility that S-phase cells may be particularly susceptible to these actions.

Dataset Information

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

Publications

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

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