Elevating SOX2 levels deleteriously affects the growth of medulloblastoma and glioblastoma cells

PLoS One. 2012;7(8):e44087. doi: 10.1371/journal.pone.0044087. Epub 2012 Aug 28.

Abstract

Medulloblastomas and glioblastomas are devastating tumors that respond poorly to treatment. These tumors have been shown to express SOX2 and overexpression of SOX2 has been correlated with poor prognosis. Although knockdown of SOX2 impairs the growth and tumorigenicity of brain tumor cells, it was unclear how elevating SOX2 levels would affect their fate. Interestingly, studies conducted with neural stem cells have shown that small increases or decreases in the level of this transcription factor significantly alter their fate. Here, we report that elevating SOX2 3-fold above endogenous levels in U87 and U118 glioblastoma, and DAOY medulloblastoma cells significantly impairs their ability to proliferate. We extended these findings and determined that elevating SOX2 in DAOY cells remodels their cell-cycle profile by increasing the proportion of cells in the G1-compartment, and induces the expression of genes associated with differentiation. Furthermore, we show that elevating SOX2 leads to a dramatic induction of CD133 expression in DAOY cells, yet inhibits the ability of both CD133(+) and CD133(-) cells to form neurospheres. Together, these findings argue that SOX2 levels must be carefully controlled in glioblastomas and medulloblastomas to maintain their fate. Equally important, our data suggests that increases in the expression of SOX2 during brain tumor progression are likely to be linked closely with changes in other critical genes that work in concert with SOX2 to enhance the tumorigenicity of brain tumors. Importantly, we demonstrate that this is also likely to be true for other cancers that express SOX2. Moreover, these studies demonstrate the advantage of using inducible promoters to study the effects of SOX2 elevation, as compared to gene expression systems that rely on constitutive expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Female
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Humans
  • Male
  • Medulloblastoma / genetics*
  • Medulloblastoma / metabolism
  • Medulloblastoma / pathology
  • Peptides / genetics
  • Peptides / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • SOXB1 Transcription Factors / genetics*
  • SOXB1 Transcription Factors / metabolism

Substances

  • AC133 Antigen
  • Antigens, CD
  • Glycoproteins
  • PROM1 protein, human
  • Peptides
  • SOX2 protein, human
  • SOXB1 Transcription Factors

Grant support

This work was supported by the Nebraska Department of Health; Contract grant number: (2011–29; 2012–33). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.