Mechanisms of RASSF1A tumor suppressor gene inactivation by de novo methylation of the promoter CpG island during carcinogenesis

Silencing of tumor suppressor genes by epigenetic modification is most likely the main cause of cancer formation in somatic cells. In our previous studies, we have identified and characterized a tumor suppressor gene named RASSF1A (Ras Association domain Family 1A), which is epigenetically inactivated in a large percentage of human carcinomas. We want to elucidate the molecular mechanisms of epigenetic silencing of RASSF1A during carcinogenesis. We have created a cell culture model to investigate the mechanism of de novo methylation. In normal human mammary epithelial cells, which were grown for consecutive cell passages, we have observed a dramatic transcriptional silencing of RASSF1A and a spreading of methylation into the CpG island from both flanking regions was detected. In the senescent cells, the expression of RASSF1A was similar to the transcription levels found in breast cancer cell lines, but the methylation of the RASSF1A CpG islands was less pronounced in these epithelial cells. Our data suggest that transcriptional occlusion of RASSF1A promoter triggers its epigenetic inactivation. In this cell culture model, we will examine alterations in chromatin structure, DNA replication, RNA expression and methylation pattern of the RASSF1 gene. Furthermore we will investigate treatments, which enhance or reverse the epigenetic silencing of RASSF1A. Understanding the molecular mechanisms of epigenetic silencing during carcinogenesis may lead to novel drugs and methods for the cure of cancer and other diseases brought on by gene deregulation.
Keywords: Methylation, CpG island promoter, Tumor suppressor gene, Transcription, Chromatin structure
Domain: DNA Methylierung und Chromatin
Involved in the project: Gerd P. Pfeifer
Maria Strunnikova


1. CpG island methylation and expression of tumour-associated genes in lung carcinoma.
Dammann R, Strunnikova M, Schagdarsurengin U, Rastetter M, Papritz M, Hattenhorst UE, Hofmann HS, Silber RE, Burdach S, Hansen G. Eur J Cancer. 2005 May;41(8):1223-36.

2. Chromatin inactivation precedes de novo DNA methylation during the progressive epigenetic silencing of the RASSF1A promoter. Strunnikova M, Schagdarsurengin U, Kehlen A, Garbe JC, Stampfer MR, Dammann R. Mol Cell Biol. 2005 May;25(10):3923-33.



Prof. Dr. Reinhard Dammann
Institut für Genetik
Heinrich-Buff-Ring 58
D-35392 Gießen, Germany

Phone: +49 641-99-35462
Fax: +49 641-99-35469