Transcriptional regulation of a metastasis suppressor gene by Tip60 and β-catenin complexes

Defining the molecular strategies that integrate diverse signalling pathways in the expression of specific gene programmes that are critical in homeostasis and disease remains a central issue in biology. This is particularly pertinent in cancer biology because downregulation of tumour metastasis suppressor genes is a common occurrence 1 , 2 , and the underlying molecular mechanisms are not well established. Here we report that the downregulation of a metastasis suppressor gene, KAI1 , in prostate cancer cells involves the inhibitory actions of β-catenin, along with a reptin chromatin remodelling complex. This inhibitory function of β-catenin–reptin requires both increased β-catenin expression and recruitment of histone deacetylase activity. The coordinated actions of β-catenin–reptin components that mediate the repressive state serve to antagonize a Tip60 coactivator complex 3 , 4 , 5 , 6 , 7 , 8 that is required for activation; the balance of these opposing complexes controls the expression of KAI1 and metastatic potential. The molecular mechanisms underlying the antagonistic regulation of β-catenin–reptin and the Tip60 coactivator complexes for the metastasis suppressor gene, KAI1 , are likely to be prototypic of a selective downregulation strategy for many genes, including a subset of NF-κB target genes.