The tumor suppressor FBW7 and the vitamin D receptor are mutual cofactors.

Abstract

The E3 ligase FBW7 targets drivers of cell cycle progression such as c-MYC for proteasomal degradation. It is frequently mutated in cancer, and is a tumor suppressor. Extensive epidemiological data links vitamin D deficiency to increased incidence of several cancers, although the underlying cancer-preventive mechanisms are poorly understood. Here, we show that hormonal 1,25-dihydroxyvitamin D3 (1,25D) rapidly stimulates the interaction of the VDR with FBW7, and that of FBW7 with c-MYC. In contrast, it blocks the association of FBW7 with c-MYC antagonist MXD1. 1,25D also enhances the association of FBW7, proteasome subunits, and ubiquitin with DNA-bound c-MYC, consistent with induced degradation of c-MYC on DNA. In addition to c-MYC, 1,25D accelerates the turnover of other FBW7 target proteins. Intriguingly, FBW7 is essential for optimal VDR gene expression. It is also recruited to VDR targets genes, and its depletion attenuates 1,25D-stimulated VDR DNA binding, transactivation, and cell cycle arrest. Thus, the VDR and FBW7 are mutual cofactors, which provides a molecular basis for the cancer-preventive actions of vitamin D through accelerated turnover of FBW7 target proteins.