MYC Is a Major Determinant of Mitotic Cell Fate

Caroline Topham; Anthony Tighe; Peter Ly; Ailsa Bennett; Olivia Sloss; Louisa Nelson; Rachel A. Ridgway; David Huels; Samantha Littler; Claudia Schandl; Ying Sun; Beatrice Bechi; David J. Procter; Owen J. Sansom; Don W. Cleveland; Stephen S. Taylor

doi:10.1016/j.ccell.2015.06.001

MYC Is a Major Determinant of Mitotic Cell Fate

Caroline Topham, Anthony Tighe, Peter Ly, Ailsa Bennett, Olivia Sloss, Louisa Nelson, Rachel A. Ridgway, David Huels, Samantha Littler, Claudia Schandl, Ying Sun, Beatrice Bechi, David J. Procter, Owen J. Sansom, Don W. Cleveland, Stephen S. Taylor

Research output: Contribution to journal › Article › peer-review

100 Scopus citations

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.

Original language	English (US)
Pages (from-to)	129-140
Number of pages	12
Journal	Cancer Cell
Volume	28
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2015.06.001
State	Published - Jul 13 2015
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2015.06.001

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title = "MYC Is a Major Determinant of Mitotic Cell Fate",

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.",

author = "Caroline Topham and Anthony Tighe and Peter Ly and Ailsa Bennett and Olivia Sloss and Louisa Nelson and Ridgway, {Rachel A.} and David Huels and Samantha Littler and Claudia Schandl and Ying Sun and Beatrice Bechi and Procter, {David J.} and Sansom, {Owen J.} and Cleveland, {Don W.} and Taylor, {Stephen S.}",

note = "Funding Information: This work was supported by the Genomic Technologies and Bioimaging Core Facilities in the Faculty of Life Sciences. We thank Stefan Knapp (University of Oxford) and Bert Vogelstein (Johns Hopkins) for reagents; and Andy Hayes, Leo Zeef, Dave Spiller, Andy Sharrocks, Mike White, Gino Poulin, Donald Ogilvie, Dean Jackson, and William Weiss for useful discussions. Funding was provided by Cancer Research UK, the Medical Research Council, and the Wellcome Trust. S.S.T. is supported by a Cancer Research UK Senior Fellowship. Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

month = jul,

day = "13",

doi = "10.1016/j.ccell.2015.06.001",

language = "English (US)",

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pages = "129--140",

journal = "Cancer Cell",

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T1 - MYC Is a Major Determinant of Mitotic Cell Fate

AU - Topham, Caroline

AU - Tighe, Anthony

AU - Ly, Peter

AU - Bennett, Ailsa

AU - Sloss, Olivia

AU - Nelson, Louisa

AU - Ridgway, Rachel A.

AU - Huels, David

AU - Littler, Samantha

AU - Schandl, Claudia

AU - Sun, Ying

AU - Bechi, Beatrice

AU - Procter, David J.

AU - Sansom, Owen J.

AU - Cleveland, Don W.

AU - Taylor, Stephen S.

N1 - Funding Information: This work was supported by the Genomic Technologies and Bioimaging Core Facilities in the Faculty of Life Sciences. We thank Stefan Knapp (University of Oxford) and Bert Vogelstein (Johns Hopkins) for reagents; and Andy Hayes, Leo Zeef, Dave Spiller, Andy Sharrocks, Mike White, Gino Poulin, Donald Ogilvie, Dean Jackson, and William Weiss for useful discussions. Funding was provided by Cancer Research UK, the Medical Research Council, and the Wellcome Trust. S.S.T. is supported by a Cancer Research UK Senior Fellowship. Publisher Copyright: © 2015 The Authors.

PY - 2015/7/13

Y1 - 2015/7/13

N2 - 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.

AB - 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.

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MYC Is a Major Determinant of Mitotic Cell Fate

Abstract

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