Fbw7 regulates intestinal cell lineage commitment and is a haploinsufficient suppressor of intestinal tumourigenesis


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Rocio Sancho1,Anett Jandke1,Hayley Davis2,Markus Diefenbacher1,Ian Tomlinson2,Axel Behrens1
1Cancer Research UK - London Research Institute, London, United Kingdom,2University of Oxford, Oxford, United Kingdom

Background

The E3 ubiquitin ligase Fbw7 degrades several proto-oncogenes including c-Myc, cyclinE, Notch1 and c-Jun. Fbw7 is the fourth most frequently mutated gene in human colorectal carcinomas and has recently been described as a poor prognosis marker in human CRC, however the molecular mechanism underlying fbw7 mutations in intestinal tumour suppression is unclear.

Method

To address the role of fbw7 in intestinal homeostasis and tumourigenesis, we generated conditional knock-out mice lacking fbw7 in the intestine and evaluated the effect of fbw7 absence in normal intestinal homeostasis and in APC-mediated tumourigenesis. In parallel we analysed a cohort of human tumours bearing mutations in fbw7.

Results

Fbw7 was found to be highly expressed in the transit-amplifying progenitor cell compartment, and its deletion resulted in impaired goblet cell differentiation, and accumulation of highly proliferating progenitor cells. This function of Fbw7 was mirrored during tumour formation, since absence of Fbw7 increased proliferation and decreased differentiation of tumours triggered by aberrant Wnt signalling. Fbw7 exhibited haploinsufficiency for intestinal tumour suppression. Biallelic fbw7 inactivation increased cellular proliferation in physiological and pathological conditions in a c-Jun dependent manner. Increased Notch activity was also observed in human tumours carrying heterozygous fbw7 mutations, suggesting that fbw7 haploinsufficiency for antagonising Notch activity is conserved between human and murine cancers.

Conclusion

Fbw7 regulates intestinal biology and tumourigenesis by controlling the abundance of different substrates in a dose-dependent fashion, providing a molecular explanation for the heterozygous mutations of fbw7 observed in human CRC.