AID downregulation is a novel function of the DNMT inhibitor 5-aza-deoxycytidine

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...

Full description

Saved in:
Bibliographic Details
Published in:Oncotarget 2014-01, Vol.5 (1), p.211-223
Main Authors: Tsai, Chiou-Tsun, Yang, Pei-Ming, Chern, Ting-Rong, Chuang, Shu-Hui, Lin, Jung-Hsin, Klemm, Lars, Müschen, Markus, Chen, Ching-Chow
Format: Article
Language:English
Subjects:
Animals
Azacitidine - analogs & derivatives
Azacitidine - pharmacology
Cytidine Deaminase - metabolism
Decitabine
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors
Down-Regulation - drug effects
Enzyme Inhibitors - pharmacology
Heterografts
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Molecular Docking Simulation
Research Paper
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.1319