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

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)211-223
Number of pages13
JournalOncotarget
Volume5
Issue number1
Publication statusPublished - 2014
Externally publishedYes

    Fingerprint

Keywords

  • 5-aza-CdR
  • AID
  • DNMT1
  • Zebularine

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

Cite this

Tsai, C. T., Yang, P. M., Chern, T. R., Chuang, S. H., Lin, J. H., Klemm, L., Müschen, M., & Chen, C. C. (2014). AID downregulation is a novel function of the DNMT inhibitor 5-aza-deoxycytidine. Oncotarget, 5(1), 211-223.