BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells

Legge, Danny N.; Shephard, Alex P.; Collard, Tracey J.; Greenhough, Alexander; Chambers, Adam C.; Clarkson, Richard W.; Paraskeva, Christos; Williams, Ann C.

Abstract

To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently B-cell lymphoma 3 (BCL-3; a key regulator of NF-κB signalling) has been recognised as an important oncogenic player in solid tumours. Although reported to be over-expressed in a subset of colorectal cancers (CRC), the role of BCL-3 expression in colorectal tumorigenesis remains poorly understood. Despite evidence in the literature that BCL-3 may interact with β-catenin it is perhaps surprising, given the importance of deregulated Wnt/β-catenin signalling in colorectal carcinogenesis, that the functional significance of this interactions is not known. Here we show for the first time that BCL-3 acts as a co-activator of β-catenin/TCF-mediated transcriptional activity in colorectal cancer cells and that this interaction is important for Wnt-regulated intestinal stem cell gene expression. We demonstrate that targeting BCL-3 expression (using RNA interference) reduced β-catenin/TCF- dependent transcription and the expression of intestinal stem cell genes LGR5 and ASCL2. In contrast, the expression of canonical Wnt-targets C-Myc and Cyclin D1 remained unchanged. Furthermore, we show that BCL-3 increases the functional stem cell phenotype as shown by colorectal spheroid and tumoursphere formation in 3D culture conditions.
We propose that BCL-3 acts as a driver of the stem-cell phenotype in CRC cells potentially promoting tumour cell plasticity and therapeutic resistance. As recent reports highlight the limitations of directly targeting cancer stem cells (CSC), we believe that identifying and targeting drivers of stem cell plasticity have significant potential as new therapeutic targets.

• Journal Article Type: Article
• Acceptance Date: Feb 15, 2019
• Online Publication Date: Mar 4, 2019
• Publication Date: Mar 1, 2019
• Deposit Date: Feb 25, 2019
• Publicly Available Date: Feb 25, 2019
• Journal: DMM Disease Models and Mechanisms
• Print ISSN: 1754-8411
• Electronic ISSN: 1754-8411
• Publisher: Company of Biologists
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 3
• Article Number: dmm037697
• DOI: https://doi.org/10.1242/dmm.037697
• Keywords: NF-kappaB, LGR5, ASCL2, Wnt, spheroid, BCL3
• Public URL: https://uwe-repository.worktribe.com/output/851998
• Publisher URL: https://doi.org/10.1242/dmm.037697
• Contract Date: Feb 25, 2019