Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies

Implication for attenuated p53 response to apoptotic stresses

M. G. Lee, J. S. Huh, S. K. Chung, J. H. Lee, D. S. Byun, B. K. Ryu, M. J. Kang, K. S. Chae, S. J. Lee, C. H. Lee, J. I. Kim, S. G. Chang, Sung-Gil Chi

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)5807-5822
Number of pages16
JournalOncogene
Volume25
Issue number42
DOIs
Publication statusPublished - 2006 Sep 21

Fingerprint

Down-Regulation
Neoplasms
Urinary Bladder
Kidney
Urogenital Neoplasms
Gene Expression
Protein Stability
Etoposide
Caspases
Tumor Cell Line
Urinary Bladder Neoplasms
Epigenomics
Fluorouracil
Prostate
Prostatic Neoplasms
Cell Survival
Carcinogenesis
Apoptosis
Cell Line
Growth

Keywords

  • Apoptosis
  • CpG site
  • p53
  • Promoter hypermethylation
  • Urogenital cancer
  • XAF1

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies : Implication for attenuated p53 response to apoptotic stresses. / Lee, M. G.; Huh, J. S.; Chung, S. K.; Lee, J. H.; Byun, D. S.; Ryu, B. K.; Kang, M. J.; Chae, K. S.; Lee, S. J.; Lee, C. H.; Kim, J. I.; Chang, S. G.; Chi, Sung-Gil.

In: Oncogene, Vol. 25, No. 42, 21.09.2006, p. 5807-5822.

Research output: Contribution to journalArticle

Lee, MG, Huh, JS, Chung, SK, Lee, JH, Byun, DS, Ryu, BK, Kang, MJ, Chae, KS, Lee, SJ, Lee, CH, Kim, JI, Chang, SG & Chi, S-G 2006, 'Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: Implication for attenuated p53 response to apoptotic stresses', Oncogene, vol. 25, no. 42, pp. 5807-5822. https://doi.org/10.1038/sj.onc.1209867
Lee, M. G. ; Huh, J. S. ; Chung, S. K. ; Lee, J. H. ; Byun, D. S. ; Ryu, B. K. ; Kang, M. J. ; Chae, K. S. ; Lee, S. J. ; Lee, C. H. ; Kim, J. I. ; Chang, S. G. ; Chi, Sung-Gil. / Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies : Implication for attenuated p53 response to apoptotic stresses. In: Oncogene. 2006 ; Vol. 25, No. 42. pp. 5807-5822.
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