Kaiso overexpression promotes intestinal inflammation and potentiates intestinal tumorigenesis in ApcMin/+ mice

Constitutive Wnt/β-catenin signaling is a key contributor to colorectal cancer (CRC). Although inactivation of the tumor suppressor adenomatous polyposis coli (APC) is recognized as an early event in CRC development, it is the accumulation of multiple subsequent oncogenic insults facilitates malignant transformation. One potential contributor to colorectal carcinogenesis is the POZ-ZF transcription factor Kaiso, whose depletion extends lifespan and delays polyp onset in the widely used ApcMin/+ mouse model of intestinal cancer. These findings suggested that Kaiso potentiates intestinal tumorigenesis, but this was paradoxical as Kaiso was previously implicated as a negative regulator of Wnt/β-catenin signaling. To resolve Kaiso's role in intestinal tumorigenesis and canonical Wnt signaling, we generated a transgenic mouse model (KaisoTg/+) expressing an intestinal-specific myc-tagged Kaiso transgene. We then mated KaisoTg/+ and ApcMin/+ mice to generate KaisoTg/+:ApcMin/+ mice for further characterization. KaisoTg/+:ApcMin/+ mice exhibited reduced lifespan and increased polyp multiplicity compared to ApcMin/+ mice. Consistent with this murine phenotype, we found increased Kaiso expression in human CRC tissue, supporting a role for Kaiso in human CRC. Interestingly, Wnt target gene expression was increased in KaisoTg/+:ApcMin/+ mice, suggesting that Kaiso's function as a negative regulator of canonical Wnt signaling, as seen in Xenopus, is not maintained in this context. Notably, KaisoTg/+:ApcMin/+ mice exhibited increased inflammation and activation of NFκB signaling compared to their ApcMin/+ counterparts. This phenotype was consistent with our previous report that KaisoTg/+ mice exhibit chronic intestinal inflammation. Together our findings highlight a role for Kaiso in promoting Wnt signaling, inflammation and tumorigenesis in the mammalian intestine.