Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation.
The mechanism by which arsenic dramatically affects gene expression remains poorly understood. Here we report that prolonged exposure of acute promyelocytic leukemia NB4 cells to low levels of arsenic trioxide increased the expression of a set of genes responsible for reactive oxygen species (ROS) production. We hypothesize that arsenic-induced ROS in turn contribute partially to altered gene expression. To identify genes responsive to arsenic-induced ROS, we used microarray gene expression analysis and identified genes that responded to arsenic and hydrogen peroxide but whose response to arsenic was reversed by an ROS scavenger, N-acetyl-L-cysteine. We found that 26% of the genes significantly responsive to arsenic might have been directly altered by ROS. We further explored the mechanisms by which ROS affects gene regulation and found that the Sp1 transcription factor was oxidized by arsenic treatment, with a corresponding decrease in its in situ binding on the promoters of 3 genes, hTERT, C17, and c-Myc, whose expressions were significantly suppressed. We conclude that ROS contributed partly to arsenic-mediated gene regulation and that Sp1 oxidation contributed to gene suppression by arsenic-induced ROS.
Chou
Wen-Chien
WC
Department of Laboratory Medicine, National Taiwan University Hospital, Taipei.wchou@ha.mc.ntu.edu.tw
Chen
Hsuan-Yu
HY
Yu
Sung-Liang
SL
Cheng
Linzhao
L
Yang
Pan-Chyr
PC
Dang
Chi V
CV
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001151:Arsenic / Q000494:pharmacology*; D001798:Blood Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics
D000970:Antineoplastic Agents; D001798:Blood Proteins; C412483:CYTL1 protein, human; D016207:Cytokines; D004268:DNA-Binding Proteins; C489427:MYC protein, human; D016877:Oxidants; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; D006861:Hydrogen Peroxide; D019098:Telomerase; D001151:Arsenic