**13. Subcellular localization of Kaiso and prognosis of cancer**

As expected for a transcriptional factor, the Kaiso protein is often found in the nucleus of several tumor or non-tumor derived mammalian cell lines (Daniel, 2007). Recent studies using immunohistochemistry analysis of normal and tumor tissue revealed that Kaiso protein is predominantly localized in the cytoplasm of the cell or is totally absent, though (Soubry et al., 2005).

This seems to be unusual because Kaiso has a signal "NLS" highly conserved and required for any protein with nuclear localization. Moreover, Kaiso uses classical nuclear transport mechanisms through interaction with Importin α/β nuclear (Kelly et al., 2004). One possible explanation is that Kaiso, like other proteins or factors that normally reside in the cytoplasm, require a post-translational modification, to be targeted and translocated to the cell nucleus.

(MTA2, MMP2, and siamois CiclinD1) are linked to cell proliferation or metastasis tumor, providing a good indication of the importance, though indirect, of Kaiso in tumorigenesis

More consistent and direct data about the participation of Kaiso in the cancer development process have been recently obtained, when it has been found that Kaiso inhibits activation mediated by β-catenin of the Mmp7 gene (also known as matrilysin), which is well known for metastatic spread (Spring et al., 2005). Recently another study suggests that Kaiso can regulate TCF/LEF1-activity, via modulating HDAC1 and beta-catenin-complex formation (Iioka et al., 2009) (Figure 1f). This shows that Kaiso can directly regulate the signaling pathway of canonical Wnt / β-catenin widely known for its involvement in human tumors. Other evidence also showed that Kaiso rescues the dorsalization of the mesoderm produced by β-catenin and siamois in Xenopus laevis (Park et al., 2005). Siamois is a high mobility group (HMG)-box transcription factor that promotes the dorsalization of the mesoderm of amphibians and is a well-known target of the canonical Wnt pathway involving TCF/LEF. The Kaiso overexpression decreases the ability of TCF/LEF to interact with β-catenin, which implies that Kaiso and TCF/LEF are associated in the nucleus (Van Roy & McCrea, 2005). Other target genes of canonical Wnt pathway, such as Fos, Myc and CCND1 also appear to be directly regulated by Kaiso. On the other hand, the non-canonical Wnt pathways would also be modulated by Kaiso, at least in Xenopus, where it has been demonstrated that Kaiso

However, there is still controversy regarding the Kaiso's oncogenic or tumor suppressor role. As aforementioned, it is known that matrilysin and Wnt11 are repressed by Kaiso, and, thus, it is believed that it might act as a tumor suppressor (Dai et al., 2009). Nevertheless, Kaiso could also act as a methylation-dependent oncogene, repressing the tumor suppressor gene CDKN2A and providing increased survival of colon cancer cells (Lopes et al., 2008). The epigenetic silencing role of kaiso was approached to produce a depletion of Kaiso (by RNA interference) and an increased expression of the tumor suppressor gene CDKN2 was found, which did not affect the DNA methylation levels. As a result, the colon cancer cells were more susceptible to cell death mediated by chemotherapy (Lopes et al., 2008). It is then possible to assess the importance of kaiso as a possible

As expected for a transcriptional factor, the Kaiso protein is often found in the nucleus of several tumor or non-tumor derived mammalian cell lines (Daniel, 2007). Recent studies using immunohistochemistry analysis of normal and tumor tissue revealed that Kaiso protein is predominantly localized in the cytoplasm of the cell or is totally absent, though

This seems to be unusual because Kaiso has a signal "NLS" highly conserved and required for any protein with nuclear localization. Moreover, Kaiso uses classical nuclear transport mechanisms through interaction with Importin α/β nuclear (Kelly et al., 2004). One possible explanation is that Kaiso, like other proteins or factors that normally reside in the cytoplasm, require a post-translational modification, to be targeted and translocated to the

depletion directly directly activates the Wnt11 promoter (Kim et al, 2004).

therapeutical target to improve the efficiency of the current cancer treatments.

**13. Subcellular localization of Kaiso and prognosis of cancer** 

processes.

(Soubry et al., 2005).

cell nucleus.

However, 2009 data has shown for the first time that the subcellular localization of Kaiso in the cytoplasm of a cell is directly associated with the poor prognosis of patients with lung cancer (non-small cell), and around 85 to 95% of lung cancers are non-small cell (Dai et al., 2009). Such data shows a direct relationship between the clinical profile of patients with pathological expression of Kaiso. Therefore, evidence of changes in subcellular localization seems to be relevant to the diagnosis and prognosis of various types of human tumors.
