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

Abstract

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, 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 beta-catenin, along with a reptin chromatin remodelling complex. This inhibitory function of beta-catenin-reptin requires both increased beta-catenin expression and recruitment of histone deacetylase activity. The coordinated actions of beta-catenin-reptin components that mediate the repressive state serve to antagonize a Tip60 coactivator complex 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 beta-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-kappaB target genes.

Overexpression and role of the ATPase and putative DNA helicase RuvB-like 2 in human hepatocellular carcinoma

“…9,15 Because ␤-catenin is considered an oncogene in HCC, these results appear counterintuitive. However, recently, RUVBL2 was also found to be required for the repressing effect of ␤-catenin on the transcription of the antimetastatic gene KAI-1, 36 which is frequently down-regulated in HCC. 37 In our study of a large number of HCC samples, there were, however, no correlations between the levels of expression of RUVBL2 and ␤-catenin target genes.…”

Orchestration of chromatin-based processes: mind the TRRAP

“…This idea is supported by elegant studies from Workman's and Green's laboratories demonstrating that TRRAP/Tra1-containing complexes with either histone H3 (SAGA, GCN5, PCAF) or histone H4 (NuA4, Tip60) specificity contact transcription activators exclusively through TRRAP/Tra1 (Brown et al, 2001;Bhaumik et al, 2004). The TIP49 (Pontin) and TIP48 (Reptin) ATPase/helicase proteins, components of TRRAP-containing Tip60 complex, were found to directly associate with transcription factors such as c-Myc and b-catenin and regulate embryonic development, oncogenic transformation and metastatic potential Etard et al, 2005;Kim et al, 2005). Given its frequent presence in HAT complexes, TRRAP may also coordinate distinct chromatin-based processes involving HATs and histone acetylation.…”

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…Specifically, p50/p50 or p52/p52 homodimers can positively and negatively regulate expression of NF-kB target genes by recruiting co-activators or co-repressors. For instance, p50 appears to both positively and negatively regulate the expression of the KAI1 metastasis suppressor gene (Kim et al, 2005a). In this case, the oncoprotein bcatenin simultaneously displaces the Tip60 co-activator from the p50 complex in the KalI promoter and induces recruitment of transcriptional co-repressors, thereby converting the p50 transcriptionally active complex into a repressive complex (Kim et al, 2005a).…”