**11. Kaiso**

This protein has been recently considered revolutionary due to its multifunctional role, modulating cytoplasmic processes and fulfilling transcriptional functions. It has the specific ability to interact with methylated DNA configuring an interesting pharmacological target for molecules that participate in the interphase of the epigenome. It is also known to be decisive in the process of tumorigenesis, and cytoplasmic accumulation of this protein, such as detection by IMH, plays an important role in the prognosis of some cancers. Because of these important reasons, the impact produced by this protein in a new scenario in epigenetic cancer shall deserve greater consideration.

Kaiso protein (encoded by the zinc finger and broad-complex, tramtrack and bric-a-brac (BTB)-domain-containing 33 gene ZBTB33) is a transcriptional factor that has a BTB/POX domain for the protein-protein interaction in the amino-terminal portion and a "Zinc Finger" domain for interaction with DNA in the carboxyl-terminal portion (Collins et al., 2001; Daniel & Reynolds, 1999). Due to the aforementioned characteristics Kaiso is member of a subfamily of "zinc finger" proteins known as POZ-ZF (Daniel & Reynolds, 1999). Most members of this subfamily (POZ-ZF) transcriptional factors including, Kaiso, BCL-6, PLZF, HIC-1, FAZF, APM1, MIZ-1, ZBTB7 and champignon are involved in the process of cancer development (Bardwell & Treisman, 1994; Albagli et al., 1995; Wales et al., 1995; Schneider et al., 1997; Reuter et al., 1998; Hoatlin et al., 1999; Maeda et al., 2005a).

Kaiso protein interacts specifically with p120 catenin (p120ctn), a member of the armadillo family that owns β-catenin (Daniel & Reynolds, 1999). β-catenin and p120ctn are very similar molecules possessing the two i. domains of interaction with the cytosolic portion of cadherins and ii. the ability to translocate from the cytoplasm to the nucleus (Reynolds & Roczniak-Ferguson, 2004). A p120ctn is a regulator of the kaiso function and it is known that in the nucleus of the cell they directly modulate the action of canonical Wnt pathways and target genes of β-catenin, which is another indication of the importance of Kaiso in the development of cancer (Daniel, 2007).

downregulated, p120ctn become at least partly cytoplasmic. Cytoplasmic p120ctn is stable and modulates small GTPases by stimulating RAC and inhibiting RHO. Both small GTPases are stimulated by non-canonical Wnt signalling. f. Kaiso translocate into the nucleus and within the nucleus kaiso associates with co-repressors (N-CoR) and histone deacetylases (HDAC) and represses genes harbouring KBS (Kaiso-binding sites) or methylated CpG (mCpG) islands in their regulatory domain. Likewise, a NCoR complex with lymphoid enhancer-binding protein (LEF)/T-cell factor (TCF) represses genes with a LEF binding sequence (LBS). g. Translocation of Kaiso in the nucleus and vice versa is mainly under the influence of microenvironmental factors. h. The protein complexes involving the Wnt receptor, Gsk3 and CK1 (among others), are then taken inside the lumen of the

multivesicular bodies (MVBs), separating Gsk3 from their cytoplasmic substrates and it also

This protein has been recently considered revolutionary due to its multifunctional role, modulating cytoplasmic processes and fulfilling transcriptional functions. It has the specific ability to interact with methylated DNA configuring an interesting pharmacological target for molecules that participate in the interphase of the epigenome. It is also known to be decisive in the process of tumorigenesis, and cytoplasmic accumulation of this protein, such as detection by IMH, plays an important role in the prognosis of some cancers. Because of these important reasons, the impact produced by this protein in a new scenario in epigenetic

Kaiso protein (encoded by the zinc finger and broad-complex, tramtrack and bric-a-brac (BTB)-domain-containing 33 gene ZBTB33) is a transcriptional factor that has a BTB/POX domain for the protein-protein interaction in the amino-terminal portion and a "Zinc Finger" domain for interaction with DNA in the carboxyl-terminal portion (Collins et al., 2001; Daniel & Reynolds, 1999). Due to the aforementioned characteristics Kaiso is member of a subfamily of "zinc finger" proteins known as POZ-ZF (Daniel & Reynolds, 1999). Most members of this subfamily (POZ-ZF) transcriptional factors including, Kaiso, BCL-6, PLZF, HIC-1, FAZF, APM1, MIZ-1, ZBTB7 and champignon are involved in the process of cancer development (Bardwell & Treisman, 1994; Albagli et al., 1995; Wales et al., 1995; Schneider

Kaiso protein interacts specifically with p120 catenin (p120ctn), a member of the armadillo family that owns β-catenin (Daniel & Reynolds, 1999). β-catenin and p120ctn are very similar molecules possessing the two i. domains of interaction with the cytosolic portion of cadherins and ii. the ability to translocate from the cytoplasm to the nucleus (Reynolds & Roczniak-Ferguson, 2004). A p120ctn is a regulator of the kaiso function and it is known that in the nucleus of the cell they directly modulate the action of canonical Wnt pathways and target genes of β-catenin, which is another indication of the importance of Kaiso in the

et al., 1997; Reuter et al., 1998; Hoatlin et al., 1999; Maeda et al., 2005a).

produces the stabilization of β-catenin. APC, adenometous polyposis coli protein; BTB/POZ, broad-complex, tramtrak and bric-a-brac/poxvirus and zinc finger domain; DAAM1, Dishevelled-associated activator of morphogenesis 1; GBP, GSK3-binding protein; LRP, LDL-receptor-related protein (Wnt co-receptor). Wnt signalling pathway modified

from Van Roy & McCrea, 2005.

cancer shall deserve greater consideration.

development of cancer (Daniel, 2007).

**11. Kaiso** 

The genes transcriptionally regulated by Kaiso are matrilysin (Spring et al., 2005), c-myc and cyclin D1 (Van Roy & McCrea, 2005), all of them widely known for their involvement in cell proliferation and metastasis and all also regulated by the domain "Zinc finger" of Kaiso (Daniel, 2007). Gene Wnt11 is another important and well- known regulatory target, which belongs to the non-canonical Wnt pathways (Kim et al., 2004).

The non-canonical Wnt pathways are involved in cell polarity and cell movements of epithelial-mesenchymal transition observed during gastrulation, and also during the process of metastasis (Wallingford et al., 2002; Veeman et al., 2003). The cytoplasmic molecules involved in the transduction of non-canonical Wnt pathway are DSH (Dishevelled) and DAAM1 (Dishevelled-associated activator of morphogenesis 1) (Habas et al., 2001) that through two independent and parallel pathways lead to activation of GTPases, Rho (Marlow et al., 2002; Habas et al., 2001) and Rac (Habas et al., 2003)(Figure 1 e). Ultimately, the activation of a kinase assorted to the Rho called ROCK would be responsible for the reorganization of the cytoskeleton (Veeman et al., 2003). p120ctn regulates the cell cytoplasm proteins Rho and Rac (Van Roy & McCrea, 2005) and Kaiso would be indirectly related to processes that involve reorganization of the cytoskeleton during metastasis.

The Kaiso protein, unlike other members of the subfamily, appears to be the only factor with bimodal features in their interaction with DNA, being able to interact specifically with methylated CpG island sites and with consensus DNA sequences CTGCNA (Prokhortchouk et al., 2001; Daniel et al., 2002) (Figure 1 f). These interactions are important for the epigenetic silencing of tumor suppressor genes, which is an essential role of Kaiso in colon cancer development processes (Lopes et al., 2008).

Regarding epigenetic silencing, the Kaiso protein also acts as a histone-deacetylasedependent transcriptional repressor (Daniel, 2007). The HDAC (histone deacetylase) catalyzes the deacetylation of histones and these changes facilitate more closed chromatin conformation and restrict gene transcription. The HDAC acts as a protein complex with corepressors recruited. Some of them are directly recruited by Kaiso as NCOR1 (nuclear receptor co-repressor 1) (Yoon et al., 2003) and SIN3A (Van Roy & McCrea, 2005) (Figure 1f).

The information on repression of target genes of the canonical and non-canonical Wnt pathways, associated with cancer (including matrilysin and Wnt11) can lead us to think that the role of Kaiso in the healthy cell is that of a tumor suppressor gene.
