J Pharm Pharmacogn Res 2(Suppl. 1): S29, 2014
Special supplement with the abstract book of LATINFARMA 2013
C 011: EPIGENETIC DEREGULATION IN CANCER: THERAPEUTIC APPLICATIONS
Berdasco M.Cancer Epigenetics and Biology Program (PEBC), Institut d’ Investigació Biomedica de Bellvitge (IDIBELL), Barcelona, Spain.
Initially, cancer was thought to be solely a consequence of genetic changes in key tumor-suppressor genes and oncogenes that regulate cell proliferation, DNA repair, cell differentiation, and other homeostatic functions. However, recent research suggests that these alterations could also be due to epigenetic disruption. The study of epigenetic mechanisms in cancer, such as DNA methylation, histone modification, nucleosome positioning and micro-RNA expression, has provided extensive information about the mechanisms that contribute to the neoplastic phenotype through the regulation of expression of genes critical to transformation pathways. Regarding DNA methylation, the low level of CpG methylation in tumors compared with that in their normal-tissue counterparts and the hypermethylation of the CpG islands in the promoter regions of tumor-suppressor are accepted as being a common feature of human cancer. Due to the complexity of permutations and combinations, less is known about the patterns of histone modification disruption in human tumors. Results have shown that the CpG promoter hypermethylation event in tumor-suppressor genes in cancer cells is associated with a particular combination of histone markers and the opposite of that observed in normal cells. Aberrations in the epigenetic profiles, with respect to DNA methylation and histone modifications, could also be a consequence of genetic disruption of the epigenetic machinery, such as disruption of the histone methyltransferase NSD1 in neuroblastomas or mutations in the histone deacetylase HDAC2 in colon cancer. The deregulation of miRNA expression has also been linked to tumor progression. Changes in miRNA expression in cancer can be achieved through various mechanisms, including impairment of miRNA processing machinery, such as the recently identified mutations of TRBP2 (an essential functional partner of the DICER1 complex) in sporadic and hereditary carcinomas with microsatellite instability or by CpG hypermethylation of miRNAs with tumor-suppressor properties. The possibility of “resetting” the abnormal cancer epigenome by applying pharmacologic or genetic strategies will be also discussed.