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 downregulation
is synthetic lethal with MYC, and that MYC is a critical target of FBXW7 in
breast epithelial cells
