Tsai C.-T.Yang P.-M.Chern T.-R.Chuang S.-H.Lin J.-H.Klemm L.Müschen M.CHING-CHOW CHEN2021-05-072021-05-07201419492553https://scholars.lib.ntu.edu.tw/handle/123456789/560394Activation-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.5-aza-CdR; AID; DNMT1; Zebularine[SDGs]SDG35 aza 2' deoxycytidine; activation induced cytidine deaminase; protein p21; single stranded DNA; zebularine; 5 aza 2' deoxycytidine; AICDA (activation-induced cytidine deaminase); azacitidine; cytidine deaminase; DNA (cytosine 5) methyltransferase; DNA (cytosine-5-)-methyltransferase 1; enzyme inhibitor; antineoplastic activity; article; cancer cell; cell viability assay; down regulation; drug cytotoxicity; enzyme active site; hematopoietic cell; human; immunoblotting; immunofluorescence; immunoprecipitation; in vivo study; molecular docking; protein degradation; protein expression; reverse transcription polymerase chain reaction; tumor suppressor gene; analogs and derivatives; animal; antagonists and inhibitors; drug effects; metabolism; mouse; nonobese diabetic mouse; SCID mouse; xenograft; Animals; Azacitidine; Cytidine Deaminase; DNA (Cytosine-5-)-Methyltransferase; Down-Regulation; Enzyme Inhibitors; Heterografts; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Docking Simulationjournal article10.18632/oncotarget.1319244575562-s2.0-84893874694