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Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma

Dinesh K Singh1, Rahul K Kollipara2, Vamsidara Vemireddy3

  • 1Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Cell Reports
|January 26, 2017
PubMed

Insights

Researchers discovered a new glioblastoma (GBM) pathway driven by SOX2, independent of receptor tyrosine kinases (RTKs). This SOX2 network, involving OLIG2 and ZEB1, offers novel therapeutic targets for GBM treatment.

Area of Science:

  • Neuro-oncology
  • Cancer Biology
  • Molecular Oncology

Background:

  • Glioblastoma (GBM) research has focused on receptor tyrosine kinases (RTKs) with limited clinical success.
  • Identifying alternative GBM drivers is crucial for developing effective therapies.

Purpose of the Study:

  • To identify novel glioblastoma (GBM) drivers independent of receptor tyrosine kinases (RTKs).
  • To investigate the role of the SOX2 transcriptional network in driving glioma-initiating cells.
  • To explore therapeutic strategies targeting this SOX2 network.

Main Methods:

  • Analysis of SOX2 transcriptional regulatory network.
  • Identification of SOX2 targets, including OLIG2 and ZEB1.
  • Murine glioma models to study Sox2, Olig2, and Zeb1 activation.
  • Transformation of astrocytes via ectopic co-expression of transcription factors.
  • In vivo assessment of mithramycin as a transcriptional inhibitor.

Main Results:

  • A SOX2 transcriptional network driving glioma-initiating cells was identified, independent of RTKs.
  • Oligodendrocyte lineage transcription factor 2 (OLIG2) and zinc-finger E-box binding homeobox 1 (ZEB1) were confirmed as SOX2 targets.
  • Sox2, Olig2, and Zeb1 expression is activated by various mutation combinations in murine glioma models.
  • Ectopic co-expression of SOX2, OLIG2, and ZEB1 transformed astrocytes into glioma-initiating cells without RTK oncogenes.
  • Mithramycin downregulated SOX2 and its targets, significantly reducing GBM cell proliferation in vivo.

Conclusions:

  • The SOX2 transcriptional network is a key driver of glioblastoma, operating independently of RTKs.
  • Targeting the SOX2 network, for example with mithramycin, presents a promising therapeutic strategy for GBM.
  • This study reveals a novel mechanism of glioma initiation and offers new avenues for GBM treatment.
Keywords:
astrocytebraincancerglioblastomaoncogenestem cellstargeted therapytranscription factor

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