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MYC is a critical target of FBXW7

Lookup NU author(s): Dr Ruth Rodriguez Barrueco

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

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.

Publication metadata

Author(s): Sato M, Rodriguez-Barrueco R, Yu J, Do C, Silva JM, Gautier J

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2015

Volume: 6

Issue: 5

Pages: 3292-3305

Print publication date: 20/02/2015

Online publication date: 26/12/2014

Acceptance date: 18/12/2014

Date deposited: 01/09/2016

ISSN (electronic): 1949-2553

Publisher: Impact Journals LLC

URL: http://dx.doi.org/10.18632/oncotarget.3203

DOI: 10.18632/oncotarget.3203

PubMed id: 25669969

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