The tumor suppressor FBW7 and the vitamin D receptor are mutual cofactors in protein turnover and transcriptional regulation.

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The tumor suppressor FBW7 and the vitamin D receptor are mutual cofactors in protein turnover and transcriptional regulation.

Mol Cancer Res. 2019 Jan 03;:

Authors: Salehi-Tabar R, Memari B, Wong H, Dimitrov V, Rochel N, White JH

Abstract
The E3 ligase and tumor suppressor FBW7 targets drivers of cell cycle progression such as the oncogenic transcription factor c-MYC, for proteasomal degradation. Vitamin D signaling regulates c-MYC expression and turnover in vitro and in vivo, which is highly significant as epidemiological data link vitamin D deficiency to increased cancer incidence. We hypothesized that FBW7 and the vitamin D receptor (VDR) controlled each other's function as regulators of protein turnover and gene transcription, respectively. We found that hormonal 1,25-dihydroxyvitamin D3 (1,25D) rapidly enhanced the interaction of FBW7 with VDR and with c-MYC, whereas it blocked FBW7 binding to c-MYC antagonist MXD1. 1,25D stimulated recruitment of FBW7, SCF complex subunits and ubiquitin to DNA-bound c-MYC, consistent with 1,25D-regulated c-MYC degradation on DNA. 1,25D also accelerated the turnover of other FBW7 target proteins such as Cyclin E, c-JUN, MCL1 and AIB1, and, importantly, FBW7 depletion attenuated 1,25D-induced cell cycle arrest. Although the VDR contains a consensus FBW7 recognition motif in a VDR-specific insertion domain, its mutation did not affect FBW7-VDR interactions, and FBW7 ablation did not stabilize the VDR. Remarkably, however, FBW7 is essential for optimal VDR gene expression. In addition, FBW7 and SCF complex subunits are recruited to 1,25D-induced genes and FBW7 depletion inhibited 1,25D-dependent transactivation. Collectively, these data show that the VDR and FBW7 are mutual cofactors, and provide a mechanistic basis for the cancer-preventive actions of vitamin D. Implications: The key findings show that the vitamin D receptor and the E3 ligase FBW7 regulate each other's functions in transcriptional regulation and control of protein turnover, respectively, and provide a molecular basis for cancer-preventive actions of vitamin D.

PMID: 30606768 [PubMed - as supplied by publisher]

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