6-Thioguanine reactivates epigenetically silenced genes in acute lymphoblastic leukemia cells by facilitating proteasome-mediated degradation of DNMT1.
Thiopurines including 6-thioguanine ((S)G), 6-mercaptopurine, and azathioprine are effective anticancer agents with remarkable success in clinical practice, especially in effective treatment of acute lymphoblastic leukemia (ALL). (S)G is understood to act as a DNA hypomethylating agent in ALL cells, however, the underlying mechanism leading to global cytosine demethylation remains unclear. Here we report that (S)G treatment results in reactivation of epigenetically silenced genes in T leukemia cells. Bisulfite genomic sequencing revealed that (S)G treatment universally elicited demethylation in the promoters and/or first exons of the genes that were reactivated. (S)G treatment also attenuated the expression of histone lysine-specific demethylase 1 (LSD1), thereby stimulating lysine methylation of the DNA methylase DNMT1 and triggering its degradation via the ubiquitin-proteasomal pathway. Taken together, our findings reveal a previously uncharacterized but vital mechanistic link between (S)G treatment and DNA hypomethylation.
Department of Chemistry, University of California, Riverside, California 92521-0403, USA.
Bifeng
B
Yuan
Jing
J
Zhang
Hongxia
H
Wang
Lei
L
Xiong
Qian
Q
Cai
Tina
T
Wang
Steven
S
Jacobsen
Sriharsa
S
Pradhan
Yinsheng
Y
Wang
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000187:drug effects / Q000378:metabolism*; D019175:DNA Methylation; D015870:Gene Expression / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013866:Thioguanine / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D046988:Proteasome Endopeptidase Complex; D013866:Thioguanine
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