Epigenetic changes, particularly alterations in DMAmethylation, contribute to oncogenesis in at least tworespects. First, overall DMA methylation is reduced in tumors, which leads to aberrant gene activation andgenomic instability. Second, CpG island promoters become hypermethylated, which leads to transcriptionalsilencing and the functional inactivation of tumor suppressor genes. In addition to changes in DNAmethylation, other important epigenetic changes have been observed in human cancer, including alterationsin histone modification patterns and histone modifying enzymes. Our long-term objective is to understandthe molecular mechanisms that initiate and maintain abnormal epigenetic states in human cancer. To meetthis objective, we are utilizing cancer/germ-line (CG) antigen genes as models. CG antigens are anintriguing gene family whose aberrant expression in human cancer appears to result from epigeneticderegulation. In addition, CG antigens are HLA-restricted tumor antigens that trigger humoral and cell-mediated immune responses in cancer patients; CG antigen directed vaccines are currently in numeroushuman clinical trials. Thus, in addition to serving as a model for understanding epigenetic deregulation incancer, CG antigens are clinically relevant. We hypothesize that CG antigen gene expression isepigenetically regulated by the action of specific DNA methyltransferases (DNMTs) and histonemethyltransferases. To test this hypothesis, we will pursue four complementary and unified specific aims: 1)Determine the mechanism by which DNMTs repress CG antigen gene expression in human cancer cells; 2)Define the histone H3 tail lysine modifications that control CG antigen gene expression in human cancercells; 3) Ascertain the role of the histone methyltransferases G9a and Eu-HMTasel in CG antigen generegulation in human cancer cells; and 4) Determine whether NY-ESO-1 expression is associated with DNAhypomethylation in epithelial ovarian cancer. This study will impact public health by improving ourunderstanding of why only certain patients express clinically important cancer vaccine targets. Furthermore,this study will provide key information relevant for understanding the outcome and improving the futuredesign of clinical vaccine trials for the treatment of ovarian cancer.
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