BCL-3 enhances β-catenin signalling in colorectal tumour cells promoting a cancer stem cell phenotype

Increased nuclear BCL-3 (a key regulator of inflammation and NF-{kappa}B signalling when associated with p50 or p52 homodimers) has been reported in a subset of colorectal cancers, but its role in colorectal tumorigenesis remains poorly understood. Interestingly, recent studies have highlighted the importance of the interplay between NF-{kappa}B signalling and the Wnt/{beta}-catenin pathway in colorectal epithelial cells, reporting that non-stem cells engineered to undergo high levels of Wnt and NF-{kappa}B signalling can de-differentiate, initiating tumours in mice. Here we show that BCL-3 is an important co-activator of {beta}-catenin/TCF-mediated transcriptional activity in colorectal cancer cells, increasing expression of Wnt-regulated intestinal stem cell genes. We demonstrate RNAi-mediated BCL-3 suppression reduced {beta}-catenin/TCF-dependent transcription and the expression of intestinal stem cell genes and Wnt targets LGR5 and ASCL2. Further we show that BCL-3 promotes the stem cell phenotype in colorectal cancer cells by increasing colorectal spheroid and tumoursphere formation in 3D culture conditions. Our data suggest that targeting BCL-3 may represent an exciting new approach for CRC treatment, particularly as it acts downstream of frequently mutated APC and {beta}-catenin.