Epigenetic Regulation of , via , Alters Mitotic Spindle Polarity and Promotes Intestinal Tumorigenesis.

Both alterations to the epigenome and loss of polarity have been linked to cancer initiation, progression, and metastasis. It has previously been demonstrated that loss of the epigenetic reader protein Kaiso suppresses intestinal tumorigenesis in the mouse model, in which altered polarity plays a key role. Thus, we investigated the link between deficiency, polarity, and suppression of intestinal tumorigenesis. We used -deficient mice to conditionally delete within the intestinal epithelia and demonstrated upregulation of the spindle polarity genes and . To understand the role of , we generated mice to analyze gene expression, survival, tumor burden, and spindle orientation. analysis of the -deficient intestine revealed improper orientation of mitotic spindles and a decreased rate of cellular migration. Loss of decreased survival in mice, validating its role as a tumor suppressor in the intestine. Significantly, the increased survival of mice was shown to be dependent on expression. Taken together, these data indicate that maintenance of spindle polarity in the intestinal crypt requires appropriate regulation of expression. As loss leads to incorrect spindle orientation and a delay in cells transiting the intestinal crypt. We propose that the delayed exit from the crypt increase the window in which spontaneous mutations can become fixed, producing a "tumor-permissive" environment, without an increase in mutation rate. IMPLICATIONS: Loss of mitotic spindle polarity delays the exit of cells from the intestinal crypt and promotes a tumorigenic environment.