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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Idha Kurtsdotter
  • Danijal Topcic
  • Alexandra Karlén
  • Bhumica Singla
  • Daniel W. Hagey
  • Maria Bergsland
  • Peter Siesjö
  • Monica Nistér
  • Joseph W. Carlson
  • Veronique Lefebvre
  • Oscar Persson
  • Johan Holmberg
  • Jonas Muhr
Organisations
External organisations
  • Karolinska Institutet
  • Karolinska University Hospital
  • Cleveland Clinic Foundation
  • Ludwig Institute for Cancer Research, Uppsala branch
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)4985-4997
Number of pages13
JournalCancer Research
Volume77
Issue number18
Publication statusPublished - 2017 Sep 15
Publication categoryResearch
Peer-reviewedYes