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Hydroquinone-induced FOXP3-ADAM17-Lyn-Akt-p21 signaling axis promotes malignant progression of human leukemia U937 cells

  • Genotoxicity and Carcinogenicity
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Abstract

Hydroquinone (1,4-benzenediol; HQ), a major marrow metabolite of the leukemogen benzene, has been proven to evoke benzene-related hematological disorders and myelotoxicity in vitro and in vivo. The goal of the present study was to explore the role of FOXP3 in HQ-induced malignant progression of U937 human leukemia cells. U937 cells were treated with 5 μM HQ for 24 h, and the cells were re-suspended in serum-containing medium without HQ for 2 days. The same procedure was repeated three times, and the resulting U937/HQ cells were maintained in cultured medium containing 5 μM HQ. Proliferation and colony formation of U937/HQ cells were notably higher than those of U937 cells. Ten-eleven translocation methylcytosine dioxygenase-mediated demethylation of the Treg-specific demethylated region in FOXP3 gene resulted in higher FOXP3 expression in U937/HQ cells than in U937 cells. FOXP3-induced miR-183 expression reduced β-TrCP mRNA stability and suppressed β-TrCP-mediated Sp1 degradation, leading to up-regulation of Sp1 expression in U937/HQ cells. Sp1 up-regulation further increased ADAM17 and Lyn expression, and ADAM17 up-regulation stimulated Lyn activation in U937/HQ cells. Moreover, U937/HQ cells showed higher Lyn-mediated Akt activation and cytoplasmic p21 expression than U937 cells did. Abolishment of Akt activation decreased cytoplasmic p21 expression in U937/HQ cells. Suppression of FOXP3, ADAM17, and Lyn expression, as well as Akt inactivation, repressed proliferation and clonogenicity of U937/HQ cells. Together with the finding that cytoplasmic p21 shows anti-apoptotic and oncogenic activities in cancer cells, the present data suggest a role of FOXP3/ADAM17/Lyn/Akt/p21 signaling axis in HQ-induced hematological disorders.

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Abbreviations

AML:

Acute myeloid leukemia

ChIP:

Chromatin immunoprecipitation

CFSE:

Carboxyfluorescein succinimidyl ester

FOXP3:

Forkhead box transcription factor 3

HQ:

Hydroquinone

MDS:

Myelodysplastic syndrome

MSPCR:

Methylation-specific PCR

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

TET:

Ten-eleven translocation

Tregs:

Regulatory T cells

TSDR:

Treg-specific demethylated region

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Acknowledgments

This work was supported by grant MOST 103-2320-B110-002-MY2 from the Ministry of Science and Technology, Taiwan, ROC (to L.S. Chang).

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Authors and Affiliations

  1. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan

    Ying-Jung Chen, Wen-Hsin Liu & Long-Sen Chang

  2. Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Long-Sen Chang

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  1. Ying-Jung Chen
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Correspondence to Long-Sen Chang.

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Chen, YJ., Liu, WH. & Chang, LS. Hydroquinone-induced FOXP3-ADAM17-Lyn-Akt-p21 signaling axis promotes malignant progression of human leukemia U937 cells. Arch Toxicol 91, 983–997 (2017). https://doi.org/10.1007/s00204-016-1753-4

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