Abstract
Abstract Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Strong genetic drivers of tumorigenesis, such as loss of function of the APC tumor-suppressor gene, have been well characterized, but the role of epigenetic alterations remains poorly understood. Upregulation of DNA methyltransferases (DNMTs), including DNMT1, has been reported in various human cancers, but its functional significance to cancer is unclear. Here we report a novel mouse model of inducible Dnmt1 upregulation, bypassing the embryonic lethality of Dnmt1 overexpression. We accomplish inducible control of Dnmt1 expression by targeting the tet transcriptional activator to the endogenous Dnmt1 promoter. We combine this model with the ApcMin allele to investigate the effect of Dnmt1 upregulation on intestinal tumorigenesis. Our preliminary data suggests that Dnmt1 overexpression increases the size and multiplicity of intestinal polyps in ApcMin/+ mice. Previous work in our lab showed that DNA methylation is critical for tumor formation, but it is not known which DNA methylation alterations have functional relevance. To investigate this, we will use the Dnmt1 overexpression model to identify DNA methylation events that are responsible for the observed phenotype in ApcMin/+ mice. In summary, we describe a novel mouse model of Dnmt1 overexpression and provide preliminary evidence to suggest that such upregulation exacerbates intestinal tumorigenesis. Our investigation may yield new insights into the role of epigenetics in CRC initiation and progression and into potential epigenetic therapies. Citation Format: Nicole A. Vander Schaaf, JinA Park, Oluwasei Dina, KwangHo Lee, Peter W. Laird. The effect of Dnmt1 overexpression on intestinal tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5312.
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