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 Apc þ/min mouse model, in which altered polarity plays a key role. Thus, we investigated the link between Kaiso deficiency, polarity, and suppression of intestinal tumorigenesis. We used Kaiso-deficient mice to conditionally delete Apc within the intestinal epithelia and demonstrated upregulation of the spindle polarity genes Dlg1 and Dlgap1. To understand the role of Dlg1, we generated Villin-creApc þ/min Dlg1 flx/flx Kaiso À/y mice to analyze gene expression, survival, tumor burden, and spindle orientation. In vivo analysis of the Dlg1-deficient intestine revealed improper orientation of mitotic spindles and a decreased rate of cellular migration.Loss of Dlg1 decreased survival in Apc þ/min mice, validating its role as a tumor suppressor in the intestine. Significantly, the increased survival of Apc þ/min Kaiso y/À mice was shown to be dependent on Dlg1 expression. Taken together, these data indicate that maintenance of spindle polarity in the intestinal crypt requires appropriate regulation of Dlg1 expression. As Dlg1 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.

<p>Intestinal samples from Dlg1�IEC/�IEC (black bars) show significantly reduced Dlg1 expression compared to Wildtype (grey bars), but there is no significant changes in expression levels of other Dlg family members.</p>

<p>The loss of Dlg1 is tolerated by the small intestinal epithelium. Comparing WT and Dlg1�IEC/�IEC at death indicated there were no significant changes in (A) cellular height of crypt, number of apoptotic (B) and mitotic (C) bodies per 50 half crypts.</p>

<p>The loss of Dlg1 is tolerated by the small intestinal epithelium. Comparing WT and Dlg1�IEC/�IEC at death indicated there were no significant changes in (A) cellular height of crypt, number of apoptotic (B) and mitotic (C) bodies per 50 half crypts.</p>

<p>Relative expression analysis indicated no significant alteration to Wnt target genes expression in the intestine of the Kaiso deficient mouse. Graph of the dCt values for the fold expression change data in Fig. 1.</p>