Epigenetic remodelling of DNA in cancer
A.A. Lettini1, M. Guidoboni1, E. Fonsatti1, L. Anzalone1, E. Cortini1 and M. Maio1,2
1Division of Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy and 2Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
Offprint requests to: Michele Maio, MD, Division of Medical Oncology and Immunoterapy, Department of Oncology, University Hospital of Siena, strada delle Scotte 14, Siena 53100, Italy. e-mail: mmaio@cro.it
Summary. DNA methylation regulates gene expression in normal cells. This epigenetic mechanism acts in at least two different ways: at global genomic level by targeting repetitive sequences distributed among the whole genome (LINEs, SINEs, satellite DNA, transposons) and at local level by targeting CpG islands in promoter regions. Both epigenetic mechanisms are involved in the carcinogenetic process; however, different evidences suggest that promoter hypermethylation occurring in genes involved in cell-cycle regulation, DNA repair, cell signalling, transcription and apoptosis likely plays a prominent role.
Opposite to genetic defects DNA hypermethylation is a reversible process that can be handled through “epigenetic drugs” in a wide spectrum of tumors. Along this line, recent data have demonstrated the ability of DNA hypomethylating agents to up-regulate and/or induce the expression of genes silenced by promoter hypermethylation in cancer. Particularly relevant seems the ability of these drugs to modulate the expression of genes coding for molecules crucial for tumor immunogenicity and immune recognition of neoplastic cells by host’s immune system, such as Cancer Testis Antigens, HLA class I molecules, costimulatory molecules. These evidences, coupled to the well-known cytotoxic, pro-apoptotic, and differentiating activities of epigenetic drugs, encourage to design and to develop new therapeutic strategies able to circumvent the immune escape of neoplastic cells and to potentiate the efficacy of immunotherapy in cancer patients.
This review will provide an update on the most recent information about aberrant DNA methylation in cancer and on innovative therapeutic strategies of “epigenetic remodelling” of human malignancies, with particular attention to the immunologic and immunotherapeutic potential of this approach. Histol Histopathol 22, 1413-1424 (2007)
Key words: 5-aza-2’-deoxycytidine, Cancer, Cancer testis antigens, DNA methylation
DOI: 10.14670/HH-22.1413