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

MYC is a critical target of FBXW7.

Author information

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 Pathology, Mount Sinai School of Medicine, New York, USA.
4
Department of Biomedical Informatics, Columbia University, New York, USA.
5
Department of Genetics and Development, Columbia University, New York, USA.

Abstract

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.

PMID:
25669969
PMCID:
PMC4413654
DOI:
10.18632/oncotarget.3203
[Indexed for MEDLINE]
Free PMC Article

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