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Oncotarget. 2015 Feb 20;6(5):3292-305.

MYC is a critical target of FBXW7.

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Department of Pathology and Cell Biology, Columbia University, New York, USA.
Institute for Cancer Genetics, Columbia University, New York, USA.
Department of Pathology, Mount Sinai School of Medicine, New York, USA.
Department of Biomedical Informatics, Columbia University, New York, USA.
Department of Genetics and Development, Columbia University, New York, USA.


MYC deregulation is a driver of many human cancers. Altering the balance of MYC protein levels at the level of transcription, protein stability, or turnover is sufficient to transform cells to a tumorigenic phenotype. While direct targeting of MYC is difficult, specific genetic vulnerabilities of MYC-deregulated cells could be exploited to selectively inhibit their growth. Using a genome-wide shRNA screen, we identified 78 candidate genes, which are required for survival of human mammary epithelial cells with elevated MYC levels. Among the candidates, we validated and characterized FBXW7, a component of the SCF-like ubiquitin ligase complex that targets MYC for proteasomal degradation. Down-regulation of FBXW7 leads to synergistic accumulation of cellular and active chromatin-bound MYC, while protein levels of other FBXW7 targets appear unaffected. Over a four-week time course, continuous FBXW7 down-regulation and MYC activation together cause an accumulation of cells in S-phase and G2/M-phase of the cell cycle. Under these conditions, we also observe elevated chromatin-bound levels of CDC45, suggesting increased DNA replication stress. Consistent with these results, FBXW7 down-regulation alone decreases the survival of T47D breast cancer cells. These results establish that FBXW7 down-regulation is synthetic lethal with MYC, and that MYC is a critical target of FBXW7 in breast epithelial cells.

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