The role of vitamin D and the vitamin D receptor in TCF-4 regulation and silencing of CYP24A1
Beildeck, Marcy Ellen.
Thesis (Ph.D.)--Georgetown University, 2009.; Includes bibliographical references. Vitamin D has long been associated with a protective role against cancer. Its therapeutic index in the prevention and treatment of cancer is restricted due to dose-limiting toxicity that is related to its role in calcium mobilization. In order to identify new chemotherapeutic targets in the vitamin D pathway, we are studying its downstream effects. We have identified two novel mechanisms whereby the vitamin D receptor (VDR) and its cognate ligand, 1,25(OH)2D3, may protect against aberrant gene regulation and cell cycling.; In the process of using the mouse mammary tumor cells from VDR-null animals, we observed a lack of regulation of the classic vitamin D responsive gene, CYP24A1, which is involved in the metabolism of 1,25(OH)2D3 into inactive metabolites. This gene is 'silenced' by an epigenetic DNA methylation event, as treatment with a DNA methyltransferase inhibitor restored responsiveness. In our studies, the proximal CpG island-containing promoter of CYP24A1, is not the target of this methylation event. We propose that this is either due to an indirect methylation event, a methylation event in the distal promoter or enhancer regions of CYP24A1, or a result of dynamic methylation in this region that allows demethylation and re-expression of this gene.; In this work, we identify a novel target of the vitamin D pathway that may shed light onto the mechanism whereby vitamin D prevents cancer. We also generate a new hypothesis, as well as show evidence to reinforce previously identified, but poorly supported hypotheses in the field of epigenetics.
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