6-Thioguanine Reactivates Epigenetically Silenced Genes in Acute Lymphoblastic Leukemia Cells by Facilitating Proteasome-mediated Degradation of DNMT1

Department of Chemistry, University of California, Riverside, California 92521-0403, USA.
Cancer Research (Impact Factor: 9.33). 03/2011; 71(5):1904-11. DOI: 10.1158/0008-5472.CAN-10-3430
Source: PubMed


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.

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Available from: Bi-Feng Yuan, Oct 10, 2015
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    • "We next evaluated whether other nucleoside analogs had similar effects on IDO. As presented in Figure 5, 6-thioguanine [23], azathioprine [24] and 5-fluorouracil [25] were tested at three different documented concentrations, though none of these showed an inhibitory effect on IDO protein levels that was comparable to that by fludarabine. However, a significant downregulation of IDO protein expression was noted with azathioprine (Figure 5B). "
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