Brachyury regulates proliferation of cancer cells via a p27Kip1-dependent pathway
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Jana Jezkova1, Jason S. Williams1, Ffion Jones-Hutchins1, Stephen J. Sammut2, Simon Gollins3, Ian Cree4, Sarah Coupland5, Ramsay J. McFarlane1,6 and Jane A. Wakeman1
1 North West Cancer Research Institute, College of Natural Sciences, Bangor, Gwynedd, UK
2 School of Medical Sciences, Bangor, Gwynedd, UK
3 North Wales Cancer Treatment Centre, Betsi Cadwaladr University Health Board, Bodelwyddan, UK
4 Warwick Medical School, Clinical Sciences Building, University Hospitals Coventry and Warwickshire, Walsgrave, Coventry, UK
5 Pathology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK
6 NISCHR Cancer Genetics Biomedical Research Unit, Welsh Government, Cathays Park, Cardiff, UK
Ramsay J. McFarlane, email:
Jane A. Wakeman, email:
Keywords: Brachyury, proliferation, colorectal cancer, p27Kip1
Received: May 15, 2014 Accepted: May 19, 2014 Published: May 21, 2014
The T-box transcription factor Brachyury is expressed in a number of tumour types and has been demonstrated to have cancer inducing properties. To date, it has been linked to cancer associated induction of epithelial to mesenchymal transition, tumour metastasis and expression of markers for cancer stem-like cells. Taken together, these findings indicate that Brachyury plays an important role in the progression of cancer, although the mechanism through which it functions is poorly understood. Here we show that Brachyury regulates the potential of Brachyury-positive colorectal cancer cells to proliferate and reduced levels of Brachyury result in inhibition of proliferation, with features consistent with the cells entering a quiescent-like state. This inhibition of proliferation is dependent upon p27Kip1 demonstrating that Brachyury acts to modulate cellular proliferative fate in colorectal cancer cells in a p27Kip1-dependent manner. Analysis of patient derived colorectal tumours reveals a heterogeneous localisation of Brachyury (in the nucleolus, nucleus and cytoplasm) indicating the potential complexity of the regulatory role of Brachyury in solid colorectal tumours.
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