Format

Send to

Choose Destination
See comment in PubMed Commons below
Cancer Res. 2011 Mar 1;71(5):1904-11. doi: 10.1158/0008-5472.CAN-10-3430. Epub 2011 Jan 14.

6-Thioguanine reactivates epigenetically silenced genes in acute lymphoblastic leukemia cells by facilitating proteasome-mediated degradation of DNMT1.

Author information

1
Department of Chemistry, University of California, Riverside, California 92521-0403, USA.

Abstract

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.

PMID:
21239472
PMCID:
PMC3049985
DOI:
10.1158/0008-5472.CAN-10-3430
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center