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SOX5/6/21 prevent oncogene-driven transformation of brain stem cells

Kurtsdotter, Idha; Topcic, Danijal; Karlén, Alexandra; Singla, Bhumica; Hagey, Daniel W.; Bergsland, Maria; Siesjö, Peter LU ; Nistér, Monica; Carlson, Joseph W. and Lefebvre, Veronique, et al. (2017) In Cancer Research 77(18). p.4985-4997
Abstract

Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental... (More)

Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult.

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publication status
published
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Cancer Research
volume
77
issue
18
pages
13 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:85031404985
  • wos:000410945700022
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-17-0704
language
English
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yes
id
59a13f52-3f45-4c81-a265-574f4ad5ffb4
date added to LUP
2017-11-20 13:43:46
date last changed
2018-01-16 13:25:59
@article{59a13f52-3f45-4c81-a265-574f4ad5ffb4,
  abstract     = {<p>Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation      are      poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21)      transcription factors increase in stem cells of the subventricular zone (SVZ)      upon      oncogenic stress, whereas their expression in human glioma decreases during      malignant      progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the      cell      cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity      of      these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor      model.      Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult.</p>},
  author       = {Kurtsdotter, Idha and Topcic, Danijal and Karlén, Alexandra and Singla, Bhumica and Hagey, Daniel W. and Bergsland, Maria and Siesjö, Peter and Nistér, Monica and Carlson, Joseph W. and Lefebvre, Veronique and Persson, Oscar and Holmberg, Johan and Muhr, Jonas},
  issn         = {0008-5472},
  language     = {eng},
  month        = {09},
  number       = {18},
  pages        = {4985--4997},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {SOX5/6/21 prevent oncogene-driven transformation of brain stem cells},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-17-0704},
  volume       = {77},
  year         = {2017},
}