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Carcinogenesis Advance Access published online on March 27, 2009
Carcinogenesis, doi:10.1093/carcin/bgp073
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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 Derks1, Linda JW Bosch2, Hanneke EC Niessen3, Peter TM Moerkerk1, Sandra M van den Bosch1, Beatriz Carvalho2, Sandra Mongera2, J Willem Voncken3, Gerrit A Meijer2, Adriaan P de Bruïne1, James G Herman4,5 and Manon van Engeland1,*

1 Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, The Netherlands
3 Department of Molecular Genetics, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, The Netherlands
4 Department of TEFAF Oncology Chair, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, The Netherlands
2 Department of Pathology, VU University Medical Center, Amsterdam The Netherlands
5 Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA

* Author for correspondence: M van Engeland, Dept. of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, PO Box 616, 6200 MD Maastricht, The Netherlands, tel: +31 43 3874622, fax: +31 43 3876613, e-mail: manon.van.engeland{at}mumc.nl

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 PCR 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 x 10-9)) which 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.

Key Words: DCC promoter methylation • 18q21 • long-range epigenetic silencing

Received February 3, 2009; revised March 19, 2009; accepted March 22, 2009.


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