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Carcinogenesis Advance Access published online on October 24, 2008
Carcinogenesis, doi:10.1093/carcin/bgn240
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Specific association between the Methyl-CpG binding domain protein 2 and the hypermethylated region of the human telomerase reverse transcriptase promoter in cancer cells

Amandine Chatagnon1,*, Stéphanie Bougel2,*, Laury Perriaud1, Joël Lachuer3, Jean Benhattar2 and Robert Dante1

1 INSERM, U590, Lyon, F-69008, France
2 Institut de Pathologie, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
3 ProfileXpert/Neurobiotec Service, INSERM U842, Bron, F-69676, France

Correspondence to: Dr R. Dante, INSERM U590, Oncogenèse et Progression Tumorale, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cedex 08, FRANCE. E-mail: dante{at}univ-lyon1.fr

Human telomerase reverse transcriptase (hTERT) is expressed in most cancer cells. Paradoxically, its promoter is embedded in a hypermethylated CpG island. A short region escapes to this alteration, allowing a basal level of transcription. However, the methylation of adjacent regions may play a role in the maintenance of low hTERT expression. It is now well established that Methyl-CpG Binding Domain proteins mediate the transcriptional silencing of hypermethylated genes. The potential involvement of these proteins in the control of hTERT expression was firstly investigated in HeLa cells. Chromatin immunoprecipitation assays showed that only MBD2 associated the hypermethylated hTERT promoter. In MBD2 knockdown HeLa cells, constitutively depleted in MBD2, neither MeCP2 nor MBD1 acted as substitutes for MBD2. MBD2 depletion by transient or constitutive RNA interference led to an upregulation of hTERT transcription that can be down-regulated by expressing mouse Mbd2 protein. Our results indicate that MBD2 is specifically and directly involved in the transcriptional repression of hTERT in HeLa cells. This specific transcriptional repression was also observed in breast, liver and neuroblastoma cancer cell lines. Thus, MBD2 seems to be a general repressor of hTERT in hTERT-methylated telomerase-positive cells.

Key Words: DNA methylation • MBD2 • hTERT • transcriptional regulation • chromatin immunoprecipitation • ChIP on chip

* AC and SB equally participated to this work.

Received August 20, 2008; revised October 3, 2008; accepted October 11, 2008.


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