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A role for Kaiso–p120ctn complexes in cancer?

Key Points

  • Kaiso is a bi-modal transcriptional repressor of the broad-complex, tramtrack and bric-a-brac/poxvirus and zinc finger (BTB/POZ) subfamily of zinc finger proteins (POZ-ZF). It binds two types of DNA sequences that are located within gene-regulatory regions — methylated CpG islands, and sequence-specific sites. A number of direct gene targets have been identified for each type of DNA interaction, and Kaiso recruits co-repressor components in both contexts.

  • Kaiso's relevance to cancer progression has yet to be fully established, but is indicated by several factors. These include the known importance of DNA methylation in the inactivation of tumour-suppressor genes, Kaiso's direct functional links to gene targets of the canonical Wnt–β-catenin signalling pathway, and alterations in Kaiso's intracellular localization in response to normal or pathological microenvironments.

  • Kaiso was first discovered in association with the armadillo protein p120 catenin (p120ctn), which seems to relieve sequence-specific gene repression by dissociating Kaiso from DNA. This is partially analogous to the extensively studied relief of T-cell factor (TCF)/lymphoid enhancer-binding protein (LEF) transcriptional repression by β-catenin in response to canonical Wnt signals. However, in the context of TCF/LEF, relief from transcriptional repression does not involve dissociation from the DNA.

  • Future work needs to address whether p120ctn also modulates the repressive function of Kaiso in the context of methylated DNA and whether, within gene-regulatory regions, a functional relationship exists between the sequence-specific and methylated CpG island-binding sites of Kaiso.

  • The identification of the signalling pathways that direct the nuclear functions of p120ctn and Kaiso is also of interest. In particular, p120ctn's known interactions with the cadherin cell–cell adhesion complex, including its associated kinases and phosphatases, with the Rho-family GTPases and with several cytoskeletal components are discussed.

Abstract

Kaiso belongs to the zinc finger and broad-complex, tramtrack and bric-a-brac/poxvirus and zinc finger (BTB/POZ) protein family that has been implicated in tumorigenesis. Kaiso was first discovered in a complex with the armadillo-domain protein p120ctn and later shown to function as a transcriptional repressor. As p120ctn seems to relieve Kaiso-mediated repression, its altered intracellular localization in some cancer cells might result in aberrant Kaiso nuclear activity. Intriguingly, Kaiso's target genes include both methylated and sequence-specific recognition sites. The latter include genes that are modulated by the canonical Wnt (β-catenin–T-cell factor) signalling pathway. Further interest in Kaiso stems from findings that its cytoplasmic versus nuclear localization is modulated by complex cues from the microenvironment.

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Figure 1: Domain structure of representative human POZ-ZF proteins.
Figure 2: Molecular complexes of Kaiso and LEF/TCF with armadillo proteins in the nucleus.
Figure 3: Crosstalk between Kaiso and Kaiso–p120ctn complexes with Wnt signalling pathways.

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Acknowledgements

Research by F.M.v.R. was supported by the Fund for Scientific Research (FWO)–Flanders, Geconcerteerde Onderzoeksacties of Ghent University, Fortis Verzekeringen (Belgium), Interuniversity Attraction Poles Programme of the Belgian Science Policy, and the Sixth Framework Programme of the European Union (BRECOSM). P.D.M. was supported by the National Institutes of Health and an Institutional Research Grant. F.M.v.R. and P.D.M. acknowledge many Kaiso and p120ctn researchers for helpful discussions. Dominique Vlieghe is acknowledged for the bioinformatic analysis of POZ-ZF proteins.

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Correspondence to Frans M. van Roy.

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DATABASES

Entrez Gene

β-catenin

E-cadherin

Groucho

HIC1

Kaiso

Kaiso-like 1

LEF

MBD2

MTA1

MTA2

p120 catenin

Pokemon

SIN3A

ZENON

National Cancer Institute

breast cancer

hepatocellular carcinomas

non-small-cell lung cancer

prostate tumours

FURTHER INFORMATION

BioMart extraction of the human genome database

BTB/POZ domain entry on Pfam

BTB/POZ protein database

Entrez Cancer Chromosomes

Kaiso and ZENON in X. laevis

Wnt signalling pathways

Glossary

CPG ISLAND

A region of DNA with a high density of cytosine–phosphoguanine dinucleotides, which are usually located in the promoter region or the first exons of a gene. CpG islands are involved in the regulation of transcription because their methylation can lead to reduced expression or silencing of the associated gene.

CANONICAL Wnt TARGET GENES

The transcription of a specific set of genes mediated by the binding of β-catenin to one of the TCF/LEF transcription factors. This association is a result of the binding of Wnt to its cognate Frizzled/LRP coreceptor complex, which results in the downstream metabolic stabilization of β-catenin and its accumulation in the nucleus.

MORPHOLINO ANTISENSE OLIGONUCLEOTIDE

Morpholinos are distinguished by having stable phosphorodiamidate intersubunit links between bases. A morpholino is most often directed to complementary sequences adjoining the translational start site of a selected mRNA target — thereby blocking ribosome assembly and protein translation — or to span an RNA splice junction to block pre-mRNA processing.

GASTRULATION

During embryonic development, gastrulation is the stage that results in the formation of the three primary germ layers: ectoderm, mesoderm and endoderm.

BLASTULA

Stage of embryonic development near the end of cleavage but before gastrulation. In animals where cell division involves the whole egg, the blastula usually consists of a hollow ball of cells.

DNA BREATHING

Local denaturation and renaturation of double-stranded DNA owing to reversible binding by a protein, which exerts gene-replication or gene-regulatory functions in this way.

MYOTUBES

Differentiated skeletal muscle cells generated by the fusion of precursor myoblasts.

CADHERIN CIS-DIMER FORMATION

Classic cadherins such as E-cadherin are able to dimerize in two ways: in trans orientations as a molecular basis for their homophilic binding activity between juxtaposed cadherin-expressing cells, and in cis or lateral orientations between identical molecules presented on the same plasma membrane. The latter compact configuration is thought to favour the stability of cadherins and their interaction with clustered cytoskeletal elements.

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van Roy, F., McCrea, P. A role for Kaiso–p120ctn complexes in cancer?. Nat Rev Cancer 5, 956–964 (2005). https://doi.org/10.1038/nrc1752

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