AID downregulation is a novel function of the DNMT inhibitor 5-aza-deoxycytidine
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Chiou-Tsun Tsai1, Pei-Ming Yang1, Ting-Rong Chern3, Shu-Hui Chuang1, Jung-Hsin Lin2,3,4, Lars Klemm5, Markus Müschen5 and Ching-Chow Chen1
1 Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
2 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
3 Research Center for Applied Sciences, Academia Sinica, Taipei, Taiwan
4 Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan
5 Department of Laboratory Medicine, University of California San Francisco, San Francisco, California
Ching-Chow Chen, email:
Keywords: AID, 5-aza-CdR, Zebularine, DNMT1
Received: August 23, 2013 Accepted: November 23, 2013 Published: November 25, 2013
Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutation (SHM) and class switch recombination (CSR) in immunoglobulin genes. However, AID can also cause mutations in host genes and contribute to cancer progression and drug resistance. In this study, molecular docking showed the interaction of free 5-aza-CdR and Zebularine (Zeb) with AID. However, only 5-aza-CdR-incorporated ssDNA bound to the active site of AID and inhibited AID expression through proteasomal degradation. 5-aza-CdR demonstrated cytotoxicity against AID-positive and -negative hematopoietic cancer cells. In contrast, Zeb exhibited a cytotoxic effect only in AID-negative cells due to its inability to inhibit AID expression. This differential effect might be due to the DNMT1 stabilization induced by AID, thus restricting the ability of Zeb to deplete DNMT1 and induce tumor suppressor genes (TSGs), such as p21, in AID-positive cells. Moreover, the in vivo anticancer effect of 5-aza-CdR but not Zeb in AID-positive hematopoietic cancer cells was demonstrated. The study not only displays the association of AID and DNMT1 and identifies a novel biological function of AID, but also provides novel information regarding the use of DNMT inhibitors to treat AID-positive hematopoietic cancers.
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