The function of BCL9 in Wnt/beta-catenin signaling and colorectal cancer cells.
BACKGROUND
Most cases of colorectal cancer are initiated by hyperactivation of the Wnt/beta-catenin pathway due to mutations in the APC tumour suppressor, or in beta-catenin itself. A recently discovered component of this pathway is Legless, which is essential for Wnt-induced transcription during Drosophila development. Limited functional information is available for its two mammalian relatives, BCL9 and B9L/BCL9-2: like Legless, these proteins bind to beta-catenin, and RNAi-mediated depletion of B9L/BCL9-2 has revealed that this protein is required for efficient beta-catenin-mediated transcription in mammalian cell lines. No loss-of-function data are available for BCL9.


METHODS
We have used overexpression of dominant-negative forms of BCL9, and RNAi-mediated depletion, to study its function in human cell lines with elevated Wnt pathway activity, including colorectal cancer cells.


RESULTS
We found that BCL9 is required for efficient beta-catenin-mediated transcription in Wnt-stimulated HEK 293 cells, and in the SW480 colorectal cancer cell line whose Wnt pathway is active due to APC mutation. Dominant-negative mutants of BCL9 indicated that its function depends not only on its beta-catenin ligand, but also on an unknown ligand of its C-terminus. Finally, we show that BCL9 and B9L are both Wnt-inducible genes, hyperexpressed in colorectal cancer cell lines, indicating that they are part of a positive feedback loop.


CONCLUSIONS
BCL9 is required for efficient beta-catenin-mediated transcription in human cell lines whose Wnt pathway is active, including colorectal cancer cells, indicating its potential as a drug target in colorectal cancer.
de la Roche
Marc
M
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK. marcd@mrc-lmb.cam.ac.uk
Worm
Jesper
J
Bienz
Mariann
M
D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics*
C111180:BCL9 protein, human; C495498:BCL9L protein, human; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin