title: MYC is a critical target of FBXW7.
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.
authors: Department of Pathology and Cell Biology, Columbia University, New York, USA.|Institute for Cancer Genetics, Columbia University, New York, USA.
authors: Mai
authors: M
authors: Sato
authors: Institute for Cancer Genetics, Columbia University, New York, USA.|Department of Pathology, Mount Sinai School of Medicine, New York, USA.
authors: Ruth
authors: R
authors: Rodriguez-Barrueco
authors: Department of Biomedical Informatics, Columbia University, New York, USA.
authors: Jiyang
authors: J
authors: Yu
authors: Institute for Cancer Genetics, Columbia University, New York, USA.
authors: Catherine
authors: C
authors: Do
authors: 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.
authors: Jose M
authors: JM
authors: Silva
authors: Institute for Cancer Genetics, Columbia University, New York, USA.|Department of Genetics and Development, Columbia University, New York, USA.
authors: Jean
authors: J
authors: Gautier
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D042002:Chromatin Assembly and Disassembly; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D044767:Ubiquitin-Protein Ligases