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  • Oncogenomics
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Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses

Oncogene volume 25, pages 5807–5822 (2006)Cite this article

Abstract

XIAP-associated factor 1 (XAF1) is a new candidate tumor suppressor, which has been known to exert proapoptotic effects by interfering with the caspase-inhibiting activity of XIAP. To explore the XAF1's candidacy for a suppressor in urogenital tumorigenesis, we investigated the XAF1 status in a series of cancer cell lines and primary tumors derived from the bladder, kidney and prostate. Expression of XAF1 transcript was undetectable or extremely low in 60% (3/5) of bladder, 66% (10/15) of kidney, and 100% (3/3) prostate cancer cell lines. Abnormal reduction of XAF1 was also found in 33% (18/55) of primary bladder and 40% (8/20) of primary kidney tumors, and showed a correlation with advanced stage and high grade of bladder tumor. Hypermethylation at 14 CpG sites in the 5′ proximal region of the XAF1 promoter was highly prevalent in cancers versus adjacent normal or benign tissues and tightly associated with reduced gene expression. XAF1 expression enhanced the apoptotic response of tumor cells to chemotherapeutic agents, such as etoposide or 5-FU. While XAF1 expression did not influence the subcellular distribution or expression of XIAP, it elevated the protein stability of p53 and its target gene expression. Moreover, the apoptosis-sensitizing and growth suppression function of XAF1 was markedly impeded by blockade of p53 function. Collectively, our study demonstrates that epigenetic alteration of XAF1 is frequent in human urogenital cancers and may contribute to the malignant progression of tumors by rendering tumor cells a survival advantage partially through the attenuated p53 response to apoptotic stresses.

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Acknowledgements

This work was supported in part by grants from Korea Science and Engineering Foundation (R02-2003-000-10031-0), Korea Research Foundation (2003-070-C00031), and the National Cancer Center (0420230), Korea.

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  1. M-G Lee and J-S Huh: These authors contributed equally to this article.

Authors and Affiliations

  1. School of Life Sciences and Biotechnology, Korea University, Seoul, Korea

    M-G Lee, S-K Chung, J-H Lee, D-S Byun, B-K Ryu, M-J Kang, K-S Chae & S-G Chi

  2. Department of Urology, College of Medicine, Cheju National University, Cheju, Korea

    J-S Huh

  3. Department of Urology, School of Medicine, Kyung Hee University, Seoul, Korea

    S-J Lee, C-H Lee, J I Kim & S-G Chang

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  1. M-G Lee
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Correspondence to S-G Chi.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Lee, MG., Huh, JS., Chung, SK. et al. Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses. Oncogene 25, 5807–5822 (2006). https://doi.org/10.1038/sj.onc.1209867

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