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Disruption of mitochondrial oxidative phosphorylation by chidamide eradicates leukemic cells in AML

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Abstract

Purpose

Nowadays, the oxidative phosphorylation (OXPHOS) correlated with leukemogenesis and treatment response is extensive. Thus, exploration of novel approaches in disrupting OXPHOS in AML is urgently needed.

Materials and methods

Bioinformatical analysis of TCGA AML dataset was performed to identify the molecular signaling of OXPHOS. The OXPHOS level was measured through a Seahorse XFe96 cell metabolic analyzer. Flow cytometry was applied to measure mitochondrial status. Real-time qPCR and western blot were used to analyze the expression of mitochondrial or inflammatory factors. MLL-AF9-induced leukemic mice were conducted to measure the anti-leukemia effect of chidamide.

Results

Here, we reported that AML patients with high OXPHOS level were in a poor prognosis, which was associated with high expression of HDAC1/3 (TCGA). Inhibition of HDAC1/3 by chidamide inhibited cell proliferation and induced apoptotic cell death in AML cells. Intriguingly, chidamide could disrupt mitochondrial OXPHOS as assessed by inducing mitochondrial superoxide and reducing oxygen consumption rate, as well as decreasing mitochondrial ATP production. We also observed that chidamide augmented HK1 expression, while glycolysis inhibitor 2-DG could reduce the elevation of HK1 and improve the sensitivity of AML cells exposed to chidamide. Furthermore, HDAC3 was correlated with hyperinflammatory status, while chidamide could downregulate the inflammatory signaling in AML. Notably, chidamide eradicated leukemic cells in vivo and prolonged the survival time of MLL-AF9-induced AML mice.

Conclusion

Chidamide disrupted mitochondrial OXPHOS, promoted cell apoptosis and reduced inflammation in AML cells. These findings exhibited a novel mechanism that targeting OXPHOS would be a novel strategy for AML treatment.

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Data availability

The data presented in this study are available on request from the corresponding author.

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Acknowledgements

We thank Dr. Shou-Jie Wang from Center for Precision Medicine, SYSU Platform of Metabolomics for the assistance with Seahorse XF Cell Mito Stress experiment.

Funding

This study was supported by Talent Training Project of The Third Affiliated Hospital of Sun Yat-sen University.

Author information

Authors and Affiliations

  1. School of Medicine, South China University of Technology, Guangzhou, China

    Jun-Dan Wang & Jian-Yu Weng

  2. Department of Hematology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

    Jun-Dan Wang & Jian-Yu Weng

  3. Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Jun-Dan Wang, Jue-Qiong Xu & Zi-Jie Long

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  1. Jun-Dan Wang
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  2. Jue-Qiong Xu
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  3. Zi-Jie Long
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Contributions

JYW and ZJL: conceived and designed the experiments. JDW and JQX: performed the experiments. JDW analyzed the data and wrote the article. All authors revised the manuscript.

Corresponding authors

Correspondence to Zi-Jie Long or Jian-Yu Weng.

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The authors declare that they have no conflict of interest.

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The animal study was conducted with the approval of Institutional Animal Care and Use Committee.

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Supplementary Information

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12094_2023_3079_MOESM1_ESM.tif

Supplementary file1 Effects of different metabolic inhibitors with chidamide. AML cells were treated chidamide (1 μM) or/and FCCP (1 µM/2 µM) (A, E), Oligomycin (1 µM/2 µM) (B, F), Rotenone (0.5 µM/1 µM) (C, G) or Metfoemin (5 mM/10 mM) (D, H) for 24 h and CCK-8 assay was applied to detect cell viability. Data were presented as mean ± SD, *p＜0.05, **p＜0.01, ***p＜0.001 (TIF 9851 KB)

12094_2023_3079_MOESM2_ESM.tif

Supplementary file2 Relation between HDAC3 and immune cell infiltration is performed. (A) Immune cell enrichment was performed in HDAC3 high and low AML patients by ssGSEA. (B) Unsupervised clustering of immune checkpoint genes and infiltrating cells were analyzed in HDAC3 high and low groups. (C) Correlation between each infiltrating cell signature was assessed by spearman analysis. (D) Infiltrating cell infiltration abundance analysis in HDAC3 high and low groups was shown (TIF 32323 KB)

Supplementary file3 (DOCX 15 KB)

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Wang, JD., Xu, JQ., Long, ZJ. et al. Disruption of mitochondrial oxidative phosphorylation by chidamide eradicates leukemic cells in AML. Clin Transl Oncol 25, 1805–1820 (2023). https://doi.org/10.1007/s12094-023-03079-8

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  • DOI: https://doi.org/10.1007/s12094-023-03079-8

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