Frequent epigenetic inactivation of XAF1 by promotor hypermethylation in human colon cancers

Jae Young Jang, Hyo Jong Kim, Sung-Gil Chi, Kil Yeon Lee, Ki Deuk Nam, Nam Hoon Kim, Sang Kil Lee, Kwang Ro Joo, Seok Ho Dong, Byung Ho Kim, Young Woon Chang, Joung Il Lee, Rin Chang

Research output: Contribution to journalArticle

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Abstract

BACKGROUND/AIMS: X-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family that exerts antiapoptotic effects. Recently, XIAP-associated factor 1 (XAF1) and two mitochondrial proteins, Smac/ DIABLO and HtrA2, have been identified to negatively regulate the caspase-inhibiting activity of XIAP. We explored the candidacy of XAF1, Smac/DIABLO and HtrA2 as a tumor suppressor in colonic carcinogenesis. METHODS: Expression and mutation status of the genes in 10 colorectal carcinoma cell lines and 40 primary tumors were examined by quantitative PCR analysis. RESULTS: XAF1 transcript was not expressed or present at extremely low levels in 60% (6/10) of cancer cell lines whereas Smac/DIABLO and HtrA2 are normally expressed in all cell lines examined. Tumor-specific loss or reduction of XAF1 was also found in 35% (14/40) of matched tissue sets obtained from the same patients. XAF1 transcript was reactivated in all the low expressor cell lines by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Moreover, bisulfite DNA sequencing analysis for 34 CpG sites in the promoter region revealed a strong association between hypermethylation and gene silencing. Restoration of XAF1 expression resulted in enhanced apoptotic response to etoposide and 5-flurouracil, whereas knockdown of XAF1 expression by siRNA transfection significantly inhibited chemotherapeutic drug-induced apoptosis. CONCLUSIONS: XAF1 undergoes epigenetic gene silencing in a considerable proportion of human colon cancers by aberrant promoter hypermethylation, suggesting that XAF1 inactivation might be implicated in colonic tumorigenesis.

Original languageEnglish
Pages (from-to)285-293
Number of pages9
JournalThe Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi
Volume45
Issue number4
Publication statusPublished - 2005 Apr 1
Externally publishedYes

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Epigenomics
Colonic Neoplasms
Apoptosis
Cell Line
decitabine
Gene Silencing
Neoplasms
Carcinogenesis
Mitochondrial Proteins
Etoposide
Caspases
DNA Sequence Analysis
Genetic Promoter Regions
Small Interfering RNA
Transfection
Colorectal Neoplasms
Polymerase Chain Reaction
Mutation
Pharmaceutical Preparations
Genes

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Frequent epigenetic inactivation of XAF1 by promotor hypermethylation in human colon cancers. / Jang, Jae Young; Kim, Hyo Jong; Chi, Sung-Gil; Lee, Kil Yeon; Nam, Ki Deuk; Kim, Nam Hoon; Lee, Sang Kil; Joo, Kwang Ro; Dong, Seok Ho; Kim, Byung Ho; Chang, Young Woon; Lee, Joung Il; Chang, Rin.

In: The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi, Vol. 45, No. 4, 01.04.2005, p. 285-293.

Research output: Contribution to journalArticle

Jang, JY, Kim, HJ, Chi, S-G, Lee, KY, Nam, KD, Kim, NH, Lee, SK, Joo, KR, Dong, SH, Kim, BH, Chang, YW, Lee, JI & Chang, R 2005, 'Frequent epigenetic inactivation of XAF1 by promotor hypermethylation in human colon cancers', The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi, vol. 45, no. 4, pp. 285-293.
Jang, Jae Young ; Kim, Hyo Jong ; Chi, Sung-Gil ; Lee, Kil Yeon ; Nam, Ki Deuk ; Kim, Nam Hoon ; Lee, Sang Kil ; Joo, Kwang Ro ; Dong, Seok Ho ; Kim, Byung Ho ; Chang, Young Woon ; Lee, Joung Il ; Chang, Rin. / Frequent epigenetic inactivation of XAF1 by promotor hypermethylation in human colon cancers. In: The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi. 2005 ; Vol. 45, No. 4. pp. 285-293.
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abstract = "BACKGROUND/AIMS: X-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family that exerts antiapoptotic effects. Recently, XIAP-associated factor 1 (XAF1) and two mitochondrial proteins, Smac/ DIABLO and HtrA2, have been identified to negatively regulate the caspase-inhibiting activity of XIAP. We explored the candidacy of XAF1, Smac/DIABLO and HtrA2 as a tumor suppressor in colonic carcinogenesis. METHODS: Expression and mutation status of the genes in 10 colorectal carcinoma cell lines and 40 primary tumors were examined by quantitative PCR analysis. RESULTS: XAF1 transcript was not expressed or present at extremely low levels in 60{\%} (6/10) of cancer cell lines whereas Smac/DIABLO and HtrA2 are normally expressed in all cell lines examined. Tumor-specific loss or reduction of XAF1 was also found in 35{\%} (14/40) of matched tissue sets obtained from the same patients. XAF1 transcript was reactivated in all the low expressor cell lines by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Moreover, bisulfite DNA sequencing analysis for 34 CpG sites in the promoter region revealed a strong association between hypermethylation and gene silencing. Restoration of XAF1 expression resulted in enhanced apoptotic response to etoposide and 5-flurouracil, whereas knockdown of XAF1 expression by siRNA transfection significantly inhibited chemotherapeutic drug-induced apoptosis. CONCLUSIONS: XAF1 undergoes epigenetic gene silencing in a considerable proportion of human colon cancers by aberrant promoter hypermethylation, suggesting that XAF1 inactivation might be implicated in colonic tumorigenesis.",
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T1 - Frequent epigenetic inactivation of XAF1 by promotor hypermethylation in human colon cancers

AU - Jang, Jae Young

AU - Kim, Hyo Jong

AU - Chi, Sung-Gil

AU - Lee, Kil Yeon

AU - Nam, Ki Deuk

AU - Kim, Nam Hoon

AU - Lee, Sang Kil

AU - Joo, Kwang Ro

AU - Dong, Seok Ho

AU - Kim, Byung Ho

AU - Chang, Young Woon

AU - Lee, Joung Il

AU - Chang, Rin

PY - 2005/4/1

Y1 - 2005/4/1

N2 - BACKGROUND/AIMS: X-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family that exerts antiapoptotic effects. Recently, XIAP-associated factor 1 (XAF1) and two mitochondrial proteins, Smac/ DIABLO and HtrA2, have been identified to negatively regulate the caspase-inhibiting activity of XIAP. We explored the candidacy of XAF1, Smac/DIABLO and HtrA2 as a tumor suppressor in colonic carcinogenesis. METHODS: Expression and mutation status of the genes in 10 colorectal carcinoma cell lines and 40 primary tumors were examined by quantitative PCR analysis. RESULTS: XAF1 transcript was not expressed or present at extremely low levels in 60% (6/10) of cancer cell lines whereas Smac/DIABLO and HtrA2 are normally expressed in all cell lines examined. Tumor-specific loss or reduction of XAF1 was also found in 35% (14/40) of matched tissue sets obtained from the same patients. XAF1 transcript was reactivated in all the low expressor cell lines by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Moreover, bisulfite DNA sequencing analysis for 34 CpG sites in the promoter region revealed a strong association between hypermethylation and gene silencing. Restoration of XAF1 expression resulted in enhanced apoptotic response to etoposide and 5-flurouracil, whereas knockdown of XAF1 expression by siRNA transfection significantly inhibited chemotherapeutic drug-induced apoptosis. CONCLUSIONS: XAF1 undergoes epigenetic gene silencing in a considerable proportion of human colon cancers by aberrant promoter hypermethylation, suggesting that XAF1 inactivation might be implicated in colonic tumorigenesis.

AB - BACKGROUND/AIMS: X-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family that exerts antiapoptotic effects. Recently, XIAP-associated factor 1 (XAF1) and two mitochondrial proteins, Smac/ DIABLO and HtrA2, have been identified to negatively regulate the caspase-inhibiting activity of XIAP. We explored the candidacy of XAF1, Smac/DIABLO and HtrA2 as a tumor suppressor in colonic carcinogenesis. METHODS: Expression and mutation status of the genes in 10 colorectal carcinoma cell lines and 40 primary tumors were examined by quantitative PCR analysis. RESULTS: XAF1 transcript was not expressed or present at extremely low levels in 60% (6/10) of cancer cell lines whereas Smac/DIABLO and HtrA2 are normally expressed in all cell lines examined. Tumor-specific loss or reduction of XAF1 was also found in 35% (14/40) of matched tissue sets obtained from the same patients. XAF1 transcript was reactivated in all the low expressor cell lines by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Moreover, bisulfite DNA sequencing analysis for 34 CpG sites in the promoter region revealed a strong association between hypermethylation and gene silencing. Restoration of XAF1 expression resulted in enhanced apoptotic response to etoposide and 5-flurouracil, whereas knockdown of XAF1 expression by siRNA transfection significantly inhibited chemotherapeutic drug-induced apoptosis. CONCLUSIONS: XAF1 undergoes epigenetic gene silencing in a considerable proportion of human colon cancers by aberrant promoter hypermethylation, suggesting that XAF1 inactivation might be implicated in colonic tumorigenesis.

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