E3 ubiquitin ligase FBW7α inhibits cholangiocarcinoma cell proliferation by downregulating c-Myc and cyclin E.

FBW7 (F-box and WD repeat domain-containing 7), also known as CDC4, AGO and SEL10, is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type E3 ubiquitin ligase. It is a recognized tumor suppressor because it targets multiple oncoproteins for ubiquitination-mediated destruction and its mutations are frequently identified in a variety of human malignancies. However, the function of FBW7 in proliferation of cholangiocarcinoma (CCA) remains unknown. We found that overexpression of FBW7α induced CCA cell arrest in G1 phase of cell cycle and inhibited cell proliferation in vitro and CCA xenograft tumor growth, suggesting that FBW7α is a tumor suppressor in CCA progression. Overxpression of FBW7α resulted in the protein degradation of its substrates such as c-Myc and cyclin E which promote CCA cell proliferation. Restoration of the expression of c-Myc, but not cyclin E, rescued the proliferation of FBW7α-overexpression CCA cells. These results suggest that FBW7α plays an essential inhibitory role in CCA progression, indicating that targeting FBW7α substrate c-Myc may be a potential strategy for CCA treatment.