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 | |
| State | Published - May 10 2016 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Genetics
- Developmental Biology
- Cell Biology
Cite this
}
Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells. / Braune, Eike Benjamin; Tsoi, Yat Long; Phoon, Yee Peng; Landor, Sebastian; Silva Cascales, Helena; Ramsköld, Daniel; Deng, Qiaolin; Lindqvist, Arne; Lian, Xiaojun; Sahlgren, Cecilia; Jin, Shao Bo; Lendahl, Urban.
In: Stem Cell Reports, Vol. 6, No. 5, 10.05.2016, p. 643-651.Research output: Contribution to journal › Article
TY - JOUR
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
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.
UR - http://www.scopus.com/inward/record.url?scp=84962774263&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84962774263&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2016.03.004
DO - 10.1016/j.stemcr.2016.03.004
M3 - Article
C2 - 27066863
AN - SCOPUS:84962774263
VL - 6
SP - 643
EP - 651
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 5
ER -