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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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
Enheter & grupper
Externa organisationer
  • Karolinska Institute
  • Karolinska University Hospital
  • Cleveland Clinic
  • Ludwig Institute for Cancer Research, Uppsala branch
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)4985-4997
Antal sidor13
TidskriftCancer Research
Volym77
Utgivningsnummer18
StatusPublished - 2017 sep 15
PublikationskategoriForskning
Peer review utfördJa