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

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Inactivation of tumor suppressor genes by epigenetic silencing is most likely the main cause of cancer formation in somatic cells. Still the responsible mechanisms remain unsolved. We want to elucidate the molecular mechanisms of epigenetic silencing in neoplastic lesions. In our previous studies, we have identified and cloned a new tumor suppressor gene named RASSF1A (Ras ASSociation domain Family 1A), which has homology to a mammalian Ras effector. RASSF1A is epigenetically inactivated in a large percentage of human carcinomas. Loss of RASSF1A expression is one of the most common and earliest events in the pathogenesis of lung cancer and other solid tumors. We want to reveal the mechanisms of epigenetic inactivation of RASSF1A during tumorigenesis. Therefore we will create a cell culture model to examine the mechanism of de novo methylation. Human mammary epithelial cells will be grown under conditions, which cause genomic changes. We will examine changes in chromatin structure, DNA replication, RNA expression and methylation pattern of the RASSF1 gene. Cells will be treated with carcinogens and the epigenetic silencing effect on RASSF1A expression will be tested. Understanding the molecular mechanisms of epigenetic inactivation in cancer may lead to novel drugs and methods for the cure of cancer and other diseases brought on by gene misregulation.