Elevating SOX2 Levels Deleteriously Affects the Growth of Medulloblastoma and Glioblastoma Cells

Jesse L. Cox, Phillip J. Wilder, Michelle Desler, A Angie Rizzino

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere44087
JournalPloS one
Volume7
Issue number8
DOIs
StatePublished - Aug 28 2012

Fingerprint

Medulloblastoma
Glioblastoma
Tumors
neoplasms
Growth
Brain
Brain Neoplasms
brain
cells
Genes
Cells
gene expression
Gene Expression
Neoplasms
Stem cells
Neural Stem Cells
Gene expression
prognosis
stem cells
cell cycle

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Elevating SOX2 Levels Deleteriously Affects the Growth of Medulloblastoma and Glioblastoma Cells. / Cox, Jesse L.; Wilder, Phillip J.; Desler, Michelle; Rizzino, A Angie.

In: PloS one, Vol. 7, No. 8, e44087, 28.08.2012.

Research output: Contribution to journalArticle

Cox, Jesse L. ; Wilder, Phillip J. ; Desler, Michelle ; Rizzino, A Angie. / Elevating SOX2 Levels Deleteriously Affects the Growth of Medulloblastoma and Glioblastoma Cells. In: PloS one. 2012 ; Vol. 7, No. 8.
@article{0995058ecdac4fc290a2e21f76856b48,
title = "Elevating SOX2 Levels Deleteriously Affects the Growth of Medulloblastoma and Glioblastoma Cells",
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.",
author = "Cox, {Jesse L.} and Wilder, {Phillip J.} and Michelle Desler and Rizzino, {A Angie}",
year = "2012",
month = "8",
day = "28",
doi = "10.1371/journal.pone.0044087",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Elevating SOX2 Levels Deleteriously Affects the Growth of Medulloblastoma and Glioblastoma Cells

AU - Cox, Jesse L.

AU - Wilder, Phillip J.

AU - Desler, Michelle

AU - Rizzino, A Angie

PY - 2012/8/28

Y1 - 2012/8/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84865504366&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865504366&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0044087

DO - 10.1371/journal.pone.0044087

M3 - Article

C2 - 22937156

AN - SCOPUS:84865504366

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e44087

ER -