Dancing from bottoms up - Roles of the POZ-ZF transcription factor Kaiso in Cancer

Abstract

The POZ-ZF transcription factor Kaiso was discovered two decades ago as a binding partner for p120^ctn. Since its discovery, roles for Kaiso in diverse biological processes (epithelial-to-mesenchymal transition, apoptosis, inflammation) and several signalling pathways (Wnt/β-catenin, TGFβ, EGFR, Notch) have emerged. While Kaiso's biological role in normal tissues has yet to be fully elucidated, Kaiso has been increasingly implicated in multiple human cancers including colon, prostate, ovarian, lung, breast and chronic myeloid leukemia. In the majority of human cancers investigated to date, high Kaiso expression correlates with aggressive tumor characteristics including proliferation and metastasis, and/or poor prognosis. More recently, interest in Kaiso stems from its apparent correlation with racial disparities in breast and prostate cancer incidence and survival outcomes in people of African Ancestry. This review discusses Kaiso's role in various cancers, and Kaiso's potential for driving racial disparities in incidence and/or outcomes in people of African ancestry.

Keywords: EMT; Inflammation; Kaiso; POZ-ZF transcription factors; Racial disparities in Cancer.

Figure 1:. Kaiso as a transcriptional activator and repressor.

(A) Kaiso possesses a BTB/POZ protein-protein interaction domain and three DNA-binding ZFs. (B) Kaiso negatively regulates expression of many genes in a methylation-dependent manner but also positively regulates other genes via the core KBS. (C) Kaiso also switches between an activator or repressor dependent on its SUMOylation status. When SUMOylated, Kaiso acts as an activator but when de-SUMOylated, Kaiso acts as a repressor. Moreover, when Kaiso interacts with wild-type p53, it was found to activate pro-apoptotic genes whereas when associated with mutant p53, Kaiso repressed pro-apoptotic genes.

Figure 2.. Kaiso regulates several tumor-related processes as defined by Hanahan & Weinberg

[27]. Kaiso activates tumor cell invasion and metastasis via regulation of TGFβ signalling, miR-200 family and E-cadherin expression. Kaiso sustains proliferative signalling through Cyclin-D1, Myc, Ki-67 and PCNA. As observed with several mouse models, Kaiso promotes intestinal inflammation. Kaiso is also implicated in resisting cell death through the regulation of c-Caspase3, Bax and PUMA. Finally, Kaiso is implicated in genome instability through its regulation of BRCA1.

Figure 3-. Possible mechanisms of action of Kaiso in EMT.

(A) Kaiso regulates TGF-β-mediated EMT and is itself regulated by the TGFβ signaling cascade which activates the expression of other pro-metastatic genes in triple negative breast tumors. The increase in Kaiso expression by TGFβ could be via the Smad transcription complex. Kaiso also appears to function in a positive feedback loop to increase TGFβ signaling (via increased TGFβRI & II expression) through as yet unidentified mechanism(s). (B) Kaiso represses E-cadherin expression through repression of miR-200 and possibly via sequestration of p120^ctn in the nucleus. Phosphorylated p120^ctn binds Kaiso, which leads to its sequestration in the nucleus and E-cadherin degradation.