| Description |
The tumor suppressor APC is mutated in 85% of colon cancer cases. APC is necessary for normal colon homeostasis, and loss of APC function is the initiating event in colon cancer. APC is a crutial member of the β -catenin destruction complex, and it was long thought APC mutation causes disruption of this complex, removing the cell's ability to destroy excess β-catenin and activating β-catenin/Tcf/Lef-induced transcription. Recent studies, however, show that nuclear localization of β-catenin occurs only after the activation of k-ras, not during the initiation of tumorigenesis. Thus, APC must play additional roles that are disrupted when mutated to cause changes from normal colon homeostasis. In this dissertation, we utilize the apcmcr mutant zebrafish as a model to parallel the loss of APC in colon cancer to show that multiple epigenetic aberrations occur before the advent of nuclear β-catenin, showing that dysregulation of epigenetic marks correlates with the initiation of colon cancer progression. The data presented in this dissertation identify two epigenetic factors regulated by APC. We show that the histone demethylase LSD1 aberrantly represses retinoid biosynthesis, preventing terminal differentiation of the intestine. This highlights one of the epigenetic regulators that is misregulated when APC is lost and adds an epigenetic mechanism for the repression of rdh1l. We also show that in the apcmcr mutant zebrafish, retinoic acid loss causes decreased H3K27 methylation levels, adding another layer of epigenetic regulation controlled through RA. In this case, we uncover an epistatic mechanism wherein Cox-2 regulates H3K27 methylation, independent of its role in the regulation of β-catenin, when APC is mutated. We also used the developing zebrafish as a model to characterize the loss of the Ezh2, the histone methyltransferase responsible for H3K27 methylation. We show that loss of Ezh2 leads to several development phenotypes, including the loss of terminal differentiation of multiple cell types in the gut. Together, the data presented in this dissertation trace the epigenetic pathways used to both regulate retinoic acid production and used by retinoic acid to promote cellular differentiation and establish APC as a regulator of histone methylation during differentiation. |
