All-trans retinoic acid induces XAF1 expression through an interferon regulatory factor-1 element in colon cancer

Jide Wang, Ying Peng, Yun Wei Sun, Hua He, Senlin Zhu, Xiaomeng An, Ming Li, Marie C.M. Lin, Bing Zou, Harry Hua Xiang Xia, Bo Jiang, Annie O.O. Chan, Man Fung Yuen, Hsiang Fu Kung, Benjamin C.Y. Wong

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Background & Aims: X-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) is a novel tumor suppressor and interferon (IFN)-stimulated gene. All-trans retinoic acid (ATRA) exerts an antiproliferative effect on tumor cells through up-regulation of IFN regulatory factor 1 (IRF-1) and the downstream IFN-stimulated genes. The aim of this study was to determine the effect and mechanism of ATRA on XAF1 expression and the role of XAF1 in ATRA-induced growth inhibition in colon cancer. Methods: Gene expression is detected by reverse-transcription polymerase chain reaction and immunoblotting. The transcription activity of XAF1 promoter is examined by luciferase reporter assay. The activity of IFN regulatory factor binding element (IRF-E) is assessed by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Cell growth is evaluated by both in vitro and in vivo in nude mice xenografts. Results: IFN-alfa stimulates XAF1 promoter activity in the colon cancer cells Lovo and SW1116 dose-dependently. An IRF-1 binding element (IRF-E-XAF1) is found in the -30 to -38 nucleotide region upstream of the ATG initiator codon of the XAF1 gene. Site-directed mutagenesis of IRF-E-XAF1 abrogates native and IFN-induced promoter activity and binding capacity. ATRA induces XAF1 expression both in vitro and in vivo through interaction with IRF-E-XAF1. Overexpression of XAF1 increases cell susceptibility to ATRA-induced growth suppression both in vitro and in vivo. Furthermore, the effect of ATRA on XAF1 expression is independent of the promoter methylation and the subcellular distribution of XIAP. Conclusions: XAF1 participates in ATRA-induced growth suppression through IRF-1-mediated transcriptional regulation.

Original languageEnglish (US)
Pages (from-to)747-758
Number of pages12
Issue number3
StatePublished - Mar 2006
Externally publishedYes

Bibliographical note

Funding Information:
Supported by grants from the Research Grant Council of Hong Kong Special Administrative Region (HKU 7482/03M), and the Gastroenterological Research Fund of the University of Hong Kong, Hong Kong.

Copyright 2018 Elsevier B.V., All rights reserved.


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