Hydroquinone-induced FOXP3-ADAM17-Lyn-Akt-p21 signaling axis promotes malignant progression of human leukemia U937 cells.
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.
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
Ying-Jung
YJ
Chen
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
Wen-Hsin
WH
Liu
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan. lschang@mail.nsysu.edu.tw.|Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. lschang@mail.nsysu.edu.tw.
Long-Sen
LS
Chang
D000072198:ADAM17 Protein / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D007938:Leukemia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000378:metabolism; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006873:Hydroquinones; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C031927:hydroquinone
ADAM17/Lyn/Akt/p21 axis; FOXP3; Hydroquinone; Leukemia; Malignant progression