MYC is a critical target of FBXW7
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Mai Sato1,2, Ruth Rodriguez-Barrueco2,5, Jiyang Yu3, Catherine Do2, Jose M. Silva1,2,5 and Jean Gautier2,4
1 Department of Pathology and Cell Biology, Columbia University, New York, USA
2 Institute for Cancer Genetics, Columbia University, New York, USA
3 Department of Biomedical Informatics, Columbia University, New York, USA
4 Department of Genetics and Development, Columbia University, New York, USA
5 Department of Pathology, Mount Sinai School of Medicine, New York, USA
Jean Gautier, email:
Keywords: MYC, FBXW7, synthetic lethality, CDC45, MCF10A
Received: November 13, 2014 Accepted: December 18, 2014 Published: December 26, 2014
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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