Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells

Eike Benjamin Braune; Yat Long Tsoi; Yee Peng Phoon; Sebastian Landor; Helena Silva Cascales; Daniel Ramsköld; Qiaolin Deng; Arne Lindqvist; Xiaojun Lian; Cecilia Sahlgren; Shao Bo Jin; Urban Lendahl

doi:10.1016/j.stemcr.2016.03.004

Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells

Eike Benjamin Braune, Yat Long Tsoi, Yee Peng Phoon, Sebastian Landor, Helena Silva Cascales, Daniel Ramsköld, Qiaolin Deng, Arne Lindqvist, Xiaojun Lian, Cecilia Sahlgren, Shao Bo Jin, Urban Lendahl

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

29 Scopus citations

Abstract

Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL, and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1α protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1,750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a role for CSL in tumorigenesis and regulation of the cellular hypoxic response.

Original language	English (US)
Pages (from-to)	643-651
Number of pages	9
Journal	Stem Cell Reports
Volume	6
Issue number	5
DOIs	https://doi.org/10.1016/j.stemcr.2016.03.004
State	Published - May 10 2016

All Science Journal Classification (ASJC) codes

Biochemistry
Genetics
Developmental Biology
Cell Biology

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10.1016/j.stemcr.2016.03.004

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title = "Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells",

abstract = "Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL, and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1α protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1,750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a role for CSL in tumorigenesis and regulation of the cellular hypoxic response.",

author = "Braune, {Eike Benjamin} and Tsoi, {Yat Long} and Phoon, {Yee Peng} and Sebastian Landor and {Silva Cascales}, Helena and Daniel Ramsk{\"o}ld and Qiaolin Deng and Arne Lindqvist and Xiaojun Lian and Cecilia Sahlgren and Jin, {Shao Bo} and Urban Lendahl",

note = "Funding Information: We wish to thank Agneta Birgitta Andersson and the BRECT core facility for excellent assistance with the xenograft experiments. This work was financially supported by the Swedish Cancer Society , the Swedish Research Council (DBRM and Project Grant), Knut och Alice Wallenbergs Stiftelse , Karolinska Institutet (BRECT), the Swedish Cultural Foundation of Finland , and K. Albin Johansson Foundation . Publisher Copyright: {\textcopyright} 2016 The Authors.",

year = "2016",

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doi = "10.1016/j.stemcr.2016.03.004",

language = "English (US)",

volume = "6",

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T1 - Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells

AU - Braune, Eike Benjamin

AU - Tsoi, Yat Long

AU - Phoon, Yee Peng

AU - Landor, Sebastian

AU - Silva Cascales, Helena

AU - Ramsköld, Daniel

AU - Deng, Qiaolin

AU - Lindqvist, Arne

AU - Lian, Xiaojun

AU - Sahlgren, Cecilia

AU - Jin, Shao Bo

AU - Lendahl, Urban

N1 - Funding Information: We wish to thank Agneta Birgitta Andersson and the BRECT core facility for excellent assistance with the xenograft experiments. This work was financially supported by the Swedish Cancer Society , the Swedish Research Council (DBRM and Project Grant), Knut och Alice Wallenbergs Stiftelse , Karolinska Institutet (BRECT), the Swedish Cultural Foundation of Finland , and K. Albin Johansson Foundation . Publisher Copyright: © 2016 The Authors.

PY - 2016/5/10

Y1 - 2016/5/10

N2 - Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL, and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1α protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1,750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a role for CSL in tumorigenesis and regulation of the cellular hypoxic response.

AB - Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL, and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1α protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1,750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a role for CSL in tumorigenesis and regulation of the cellular hypoxic response.

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Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells

Abstract

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