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

Chiou-Tsun Tsai,Lars Klemm,Jung-Hsin Lin,Shu-Hui Chuang,Markus Müschen,Ting-Rong Chern,Ching-Chow Chen,Pei-Ming Yang

doi:10.18632/oncotarget.1319

Abstract

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.

Highlights

Activation-induced cytidine deaminase (AID), encoded by the AICDA gene, belongs to the apolipoprotein B-editing catalytic polypeptide (APOBEC) family and was originally described as a B cell–specific factor unique to activated germinal center B cells
A previous study has shown that AID targets the immunoglobulin H (IgH) switch region, which contains 5’-AGCT-3’ repeats in its core [22]
The best insertion model showed that the substituted 5-aza-cytosine inserted exactly into the small active site (Fig. 1D), while the remainder of the single-strand DNA (ssDNA) interacted with the polar surface of AID (Fig. 1D, right panel)

Summary

Introduction

AID, encoded by the AICDA gene, belongs to the apolipoprotein B-editing catalytic polypeptide (APOBEC) family and was originally described as a B cell–specific factor unique to activated germinal center B cells. During CSR, AID is recruited to the switch region to deaminate the nucleoside cytidine and convert it to uridine, causing DNA point mutations and double strand breakage [1]. This activity is essential for SHM and CSR, which generates immunoglobulin diversity after V(D)J recombination [2]. The majority of patients (85%) in the chronic phase will progress to the accelerated phase and blast crisis if untreated [9]. AID is expressed in a subset of CML patients in lymphoid blast crisis, which promotes the genetic instability of tumor suppressors and DNA repair genes through point mutations and copy number alterations. AID mutates BCR-ABL1, providing a rationale for the rapid development of imatinib resistance in blast crisis progression [6]

Methods

Results

Conclusion