Promoter CpG island hypermethylation- and H3K9me3 and H3K27me3-mediated epigenetic silencing targets the deleted in colon cancer (DCC) gene in colorectal carcinogenesis without affecting neighboring genes on chromosomal region 18q21

Sarah Derks, Linda J W Bosch, Hanneke E C Niessen, Peter T M Moerkerk, Sandra M. van den Bosch, Beatriz Carvalho, Sandra Mongera, J. Willem Voncken, Gerrit A. Meijer, Adriaan P. de Bruïne, James G. Herman, Manon van Engeland

Research output: Contribution to journalArticle

Abstract

Chromosomal loss of 18q21 is a frequent event in colorectal cancer (CRC) development, suggesting that this region harbors tumor suppressor genes (TSGs). Several candidate TSGs, among which methyl-CpG-binding domain protein 1 (MBD1), CpG-binding protein CXXC1, Sma- and Mad-related protein 4 (SMAD4), deleted in colon cancer (DCC) and methyl-CpG-binding domain protein 2 (MBD2) are closely linked on a 4-Mb DNA region on chromosome18q21. As TSGs can be epigenetically silenced, this study investigates whether MBD1, CXXC1, SMAD4, DCC and MBD2 are subject to epigenetic silencing in CRC. Methylation-specific polymerase chain reaction and sodium bisulfite sequencing of these genes show that DCC, but not MBD1, CXXC1, SMAD4 and MBD2, has promoter CpG island methylation in CRC cell lines and tissues {normal mucosa [29.5% (18/61)], adenomas [81.0% (47/58)] and carcinomas [82.7% (62/75)] (P = 8.6 × 10-9)} that is associated with reduced DCC expression, independent of 18q21 loss analyzed by multiplex ligation-dependent probe amplification. Reduced gene expression of CXXC1, SMAD4 and MBD2 correlates with 18q21 loss in CRC cell lines (P = 0.04, 0.02 and 0.02, respectively). Treatment with the demethylating agent 5-aza-2′-deoxycytidine, but not with the histone deacetylase inhibitor trichostatin A exclusively restored DCC expression in CRC cell lines. Chromatin immunoprecipitation studies reveal that the DCC promoter is marked with repressive histone-tail marks H3K9me3 and H3K27me3, whereas activity related H3K4me3 was absent. Only active epigenetic marks were detected for MBD1, CXXC1, SMAD4 and MBD2. This study demonstrates specific epigenetic silencing of DCC in CRC as a focal process not affecting neighboring genes on chromosomal region 18q21.

Original languageEnglish (US)
Pages (from-to)1041-1048
Number of pages8
JournalCarcinogenesis
Volume30
Issue number6
DOIs
StatePublished - 2009

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CpG Islands
Neoplasm Genes
Smad Proteins
Epigenomics
Colonic Neoplasms
Carcinogenesis
Colorectal Neoplasms
Carrier Proteins
Genes
Tumor Suppressor Genes
decitabine
Cell Line
Methylation
trichostatin A
Histone Code
Histone Deacetylase Inhibitors
Chromatin Immunoprecipitation
Multiplex Polymerase Chain Reaction
Adenoma
Mucous Membrane

ASJC Scopus subject areas

  • Cancer Research

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Promoter CpG island hypermethylation- and H3K9me3 and H3K27me3-mediated epigenetic silencing targets the deleted in colon cancer (DCC) gene in colorectal carcinogenesis without affecting neighboring genes on chromosomal region 18q21. / Derks, Sarah; Bosch, Linda J W; Niessen, Hanneke E C; Moerkerk, Peter T M; van den Bosch, Sandra M.; Carvalho, Beatriz; Mongera, Sandra; Voncken, J. Willem; Meijer, Gerrit A.; de Bruïne, Adriaan P.; Herman, James G.; van Engeland, Manon.

In: Carcinogenesis, Vol. 30, No. 6, 2009, p. 1041-1048.

Research output: Contribution to journalArticle

Derks, S, Bosch, LJW, Niessen, HEC, Moerkerk, PTM, van den Bosch, SM, Carvalho, B, Mongera, S, Voncken, JW, Meijer, GA, de Bruïne, AP, Herman, JG & van Engeland, M 2009, 'Promoter CpG island hypermethylation- and H3K9me3 and H3K27me3-mediated epigenetic silencing targets the deleted in colon cancer (DCC) gene in colorectal carcinogenesis without affecting neighboring genes on chromosomal region 18q21', Carcinogenesis, vol. 30, no. 6, pp. 1041-1048. https://doi.org/10.1093/carcin/bgp073
Derks, Sarah ; Bosch, Linda J W ; Niessen, Hanneke E C ; Moerkerk, Peter T M ; van den Bosch, Sandra M. ; Carvalho, Beatriz ; Mongera, Sandra ; Voncken, J. Willem ; Meijer, Gerrit A. ; de Bruïne, Adriaan P. ; Herman, James G. ; van Engeland, Manon. / Promoter CpG island hypermethylation- and H3K9me3 and H3K27me3-mediated epigenetic silencing targets the deleted in colon cancer (DCC) gene in colorectal carcinogenesis without affecting neighboring genes on chromosomal region 18q21. In: Carcinogenesis. 2009 ; Vol. 30, No. 6. pp. 1041-1048.
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abstract = "Chromosomal loss of 18q21 is a frequent event in colorectal cancer (CRC) development, suggesting that this region harbors tumor suppressor genes (TSGs). Several candidate TSGs, among which methyl-CpG-binding domain protein 1 (MBD1), CpG-binding protein CXXC1, Sma- and Mad-related protein 4 (SMAD4), deleted in colon cancer (DCC) and methyl-CpG-binding domain protein 2 (MBD2) are closely linked on a 4-Mb DNA region on chromosome18q21. As TSGs can be epigenetically silenced, this study investigates whether MBD1, CXXC1, SMAD4, DCC and MBD2 are subject to epigenetic silencing in CRC. Methylation-specific polymerase chain reaction and sodium bisulfite sequencing of these genes show that DCC, but not MBD1, CXXC1, SMAD4 and MBD2, has promoter CpG island methylation in CRC cell lines and tissues {normal mucosa [29.5{\%} (18/61)], adenomas [81.0{\%} (47/58)] and carcinomas [82.7{\%} (62/75)] (P = 8.6 × 10-9)} that is associated with reduced DCC expression, independent of 18q21 loss analyzed by multiplex ligation-dependent probe amplification. Reduced gene expression of CXXC1, SMAD4 and MBD2 correlates with 18q21 loss in CRC cell lines (P = 0.04, 0.02 and 0.02, respectively). Treatment with the demethylating agent 5-aza-2′-deoxycytidine, but not with the histone deacetylase inhibitor trichostatin A exclusively restored DCC expression in CRC cell lines. Chromatin immunoprecipitation studies reveal that the DCC promoter is marked with repressive histone-tail marks H3K9me3 and H3K27me3, whereas activity related H3K4me3 was absent. Only active epigenetic marks were detected for MBD1, CXXC1, SMAD4 and MBD2. This study demonstrates specific epigenetic silencing of DCC in CRC as a focal process not affecting neighboring genes on chromosomal region 18q21.",
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AU - Derks, Sarah

AU - Bosch, Linda J W

AU - Niessen, Hanneke E C

AU - Moerkerk, Peter T M

AU - van den Bosch, Sandra M.

AU - Carvalho, Beatriz

AU - Mongera, Sandra

AU - Voncken, J. Willem

AU - Meijer, Gerrit A.

AU - de Bruïne, Adriaan P.

AU - Herman, James G.

AU - van Engeland, Manon

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N2 - Chromosomal loss of 18q21 is a frequent event in colorectal cancer (CRC) development, suggesting that this region harbors tumor suppressor genes (TSGs). Several candidate TSGs, among which methyl-CpG-binding domain protein 1 (MBD1), CpG-binding protein CXXC1, Sma- and Mad-related protein 4 (SMAD4), deleted in colon cancer (DCC) and methyl-CpG-binding domain protein 2 (MBD2) are closely linked on a 4-Mb DNA region on chromosome18q21. As TSGs can be epigenetically silenced, this study investigates whether MBD1, CXXC1, SMAD4, DCC and MBD2 are subject to epigenetic silencing in CRC. Methylation-specific polymerase chain reaction and sodium bisulfite sequencing of these genes show that DCC, but not MBD1, CXXC1, SMAD4 and MBD2, has promoter CpG island methylation in CRC cell lines and tissues {normal mucosa [29.5% (18/61)], adenomas [81.0% (47/58)] and carcinomas [82.7% (62/75)] (P = 8.6 × 10-9)} that is associated with reduced DCC expression, independent of 18q21 loss analyzed by multiplex ligation-dependent probe amplification. Reduced gene expression of CXXC1, SMAD4 and MBD2 correlates with 18q21 loss in CRC cell lines (P = 0.04, 0.02 and 0.02, respectively). Treatment with the demethylating agent 5-aza-2′-deoxycytidine, but not with the histone deacetylase inhibitor trichostatin A exclusively restored DCC expression in CRC cell lines. Chromatin immunoprecipitation studies reveal that the DCC promoter is marked with repressive histone-tail marks H3K9me3 and H3K27me3, whereas activity related H3K4me3 was absent. Only active epigenetic marks were detected for MBD1, CXXC1, SMAD4 and MBD2. This study demonstrates specific epigenetic silencing of DCC in CRC as a focal process not affecting neighboring genes on chromosomal region 18q21.

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