MYC is a major determinant of mitotic cell fate

Topham, C; Tighe, A; Ly, P; Bennett, A; Sloss, O; Nelson, L; Ridgway, RA; Huels, D; Littler, S; Schandl, C; Sun, Y; Bechi, B; Procter, DJ; Sansom, OJ; Cleveland, DW; Taylor, SS

Abstract

Taxol and other antimitotic agents are frontline chemotherapy agents but the mechanisms responsible for patient benefit remain unclear. Following a genome-wide siRNA screen, we identified the oncogenic transcription factor Myc as a taxol sensitizer. Using time-lapse imaging to correlate mitotic behavior with cell fate, we show that Myc sensitizes cells to mitotic blockers and agents that accelerate mitotic progression. Myc achieves this by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL. Accordingly, pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells. These results open up opportunities for biomarkers and combination therapies that could enhance traditional and second-generation antimitotic agents.

• Journal Article Type: Article
• Acceptance Date: Jun 8, 2015
• Online Publication Date: Jul 13, 2015
• Publication Date: Jul 1, 2015
• Deposit Date: Dec 22, 2015
• Publicly Available Date: Apr 5, 2016
• Journal: Cancer Cell
• Print ISSN: 1535-6108
• Electronic ISSN: 1878-3686
• Publisher: Elsevier
• Volume: 28
• Issue: 1
• Pages: 129-140
• DOI: https://doi.org/10.1016/j.ccell.2015.06.001
• Publisher URL: http://dx.doi.org/10.1016/j.ccell.2015.06.001
• Related Public URLs: http://www.cell.com/cancer-cell/abstract/S1535-6108(15)00211-1