Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells

Yun Bai, Justin D. Lathia, Peisu Zhang, William Flavahan, Jeremy N. Rich, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Glioblastoma is the most prevalent primary brain tumor and is essentially universally fatal within 2 years of diagnosis. Glioblastomas contain cellular hierarchies with self-renewing glioblastoma stem cells (GSCs) that are often resistant to chemotherapy and radiation therapy. GSCs express high amounts of repressor element 1 silencing transcription factor (REST), which may contribute to their resistance to standard therapies. Telomere repeat-binding factor 2 (TRF2) stablizes telomeres and REST to maintain self-renewal of neural stem cells and tumor cells. Here we show viral vector-mediated delivery of shRNAs targeting TRF2 mRNA depletes TRF2 and REST from GSCs isolated from patient specimens. As a result, GSC proliferation is reduced and the level of proteins normally expressed by postmitotic neurons (L1CAM and β3-tubulin) is increased, suggesting that loss of TRF2 engages a cell differentiation program in the GSCs. Depletion of TRF2 also sensitizes GSCs to temozolomide, a DNA-alkylating agent currently used to treat glioblastoma. Targeting TRF2 significantly increased the survival of mice bearing GSC xenografts. These findings reveal a role for TRF2 in the maintenance of REST-associated proliferation and chemotherapy resistance of GSCs, suggesting that TRF2 is a potential therapeutic target for glioblastoma.

Original languageEnglish (US)
Pages (from-to)1687-1698
Number of pages12
JournalGLIA
Volume62
Issue number10
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Telomere-Binding Proteins
Glioblastoma
Carcinogenesis
Stem Cells
Growth
Transcriptional Silencer Elements
Transcription Factors
temozolomide
Neural Cell Adhesion Molecule L1
Drug Therapy
Neural Stem Cells
Alkylating Agents
Telomere
Tubulin
Heterografts
Brain Neoplasms

Keywords

  • Cancer stem cells
  • Glioblastoma
  • Telomeres
  • Transcriptional repression

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology

Cite this

Bai, Y., Lathia, J. D., Zhang, P., Flavahan, W., Rich, J. N., & Mattson, M. P. (2014). Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells. GLIA, 62(10), 1687-1698. https://doi.org/10.1002/glia.22708

Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells. / Bai, Yun; Lathia, Justin D.; Zhang, Peisu; Flavahan, William; Rich, Jeremy N.; Mattson, Mark P.

In: GLIA, Vol. 62, No. 10, 2014, p. 1687-1698.

Research output: Contribution to journalArticle

Bai, Y, Lathia, JD, Zhang, P, Flavahan, W, Rich, JN & Mattson, MP 2014, 'Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells', GLIA, vol. 62, no. 10, pp. 1687-1698. https://doi.org/10.1002/glia.22708
Bai, Yun ; Lathia, Justin D. ; Zhang, Peisu ; Flavahan, William ; Rich, Jeremy N. ; Mattson, Mark P. / Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells. In: GLIA. 2014 ; Vol. 62, No. 10. pp. 1687-1698.
@article{6af086f542d849db8cdeda8823bcd413,
title = "Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells",
abstract = "Glioblastoma is the most prevalent primary brain tumor and is essentially universally fatal within 2 years of diagnosis. Glioblastomas contain cellular hierarchies with self-renewing glioblastoma stem cells (GSCs) that are often resistant to chemotherapy and radiation therapy. GSCs express high amounts of repressor element 1 silencing transcription factor (REST), which may contribute to their resistance to standard therapies. Telomere repeat-binding factor 2 (TRF2) stablizes telomeres and REST to maintain self-renewal of neural stem cells and tumor cells. Here we show viral vector-mediated delivery of shRNAs targeting TRF2 mRNA depletes TRF2 and REST from GSCs isolated from patient specimens. As a result, GSC proliferation is reduced and the level of proteins normally expressed by postmitotic neurons (L1CAM and β3-tubulin) is increased, suggesting that loss of TRF2 engages a cell differentiation program in the GSCs. Depletion of TRF2 also sensitizes GSCs to temozolomide, a DNA-alkylating agent currently used to treat glioblastoma. Targeting TRF2 significantly increased the survival of mice bearing GSC xenografts. These findings reveal a role for TRF2 in the maintenance of REST-associated proliferation and chemotherapy resistance of GSCs, suggesting that TRF2 is a potential therapeutic target for glioblastoma.",
keywords = "Cancer stem cells, Glioblastoma, Telomeres, Transcriptional repression",
author = "Yun Bai and Lathia, {Justin D.} and Peisu Zhang and William Flavahan and Rich, {Jeremy N.} and Mattson, {Mark P.}",
year = "2014",
doi = "10.1002/glia.22708",
language = "English (US)",
volume = "62",
pages = "1687--1698",
journal = "GLIA",
issn = "0894-1491",
publisher = "John Wiley and Sons Inc.",
number = "10",

}

TY - JOUR

T1 - Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells

AU - Bai, Yun

AU - Lathia, Justin D.

AU - Zhang, Peisu

AU - Flavahan, William

AU - Rich, Jeremy N.

AU - Mattson, Mark P.

PY - 2014

Y1 - 2014

N2 - Glioblastoma is the most prevalent primary brain tumor and is essentially universally fatal within 2 years of diagnosis. Glioblastomas contain cellular hierarchies with self-renewing glioblastoma stem cells (GSCs) that are often resistant to chemotherapy and radiation therapy. GSCs express high amounts of repressor element 1 silencing transcription factor (REST), which may contribute to their resistance to standard therapies. Telomere repeat-binding factor 2 (TRF2) stablizes telomeres and REST to maintain self-renewal of neural stem cells and tumor cells. Here we show viral vector-mediated delivery of shRNAs targeting TRF2 mRNA depletes TRF2 and REST from GSCs isolated from patient specimens. As a result, GSC proliferation is reduced and the level of proteins normally expressed by postmitotic neurons (L1CAM and β3-tubulin) is increased, suggesting that loss of TRF2 engages a cell differentiation program in the GSCs. Depletion of TRF2 also sensitizes GSCs to temozolomide, a DNA-alkylating agent currently used to treat glioblastoma. Targeting TRF2 significantly increased the survival of mice bearing GSC xenografts. These findings reveal a role for TRF2 in the maintenance of REST-associated proliferation and chemotherapy resistance of GSCs, suggesting that TRF2 is a potential therapeutic target for glioblastoma.

AB - Glioblastoma is the most prevalent primary brain tumor and is essentially universally fatal within 2 years of diagnosis. Glioblastomas contain cellular hierarchies with self-renewing glioblastoma stem cells (GSCs) that are often resistant to chemotherapy and radiation therapy. GSCs express high amounts of repressor element 1 silencing transcription factor (REST), which may contribute to their resistance to standard therapies. Telomere repeat-binding factor 2 (TRF2) stablizes telomeres and REST to maintain self-renewal of neural stem cells and tumor cells. Here we show viral vector-mediated delivery of shRNAs targeting TRF2 mRNA depletes TRF2 and REST from GSCs isolated from patient specimens. As a result, GSC proliferation is reduced and the level of proteins normally expressed by postmitotic neurons (L1CAM and β3-tubulin) is increased, suggesting that loss of TRF2 engages a cell differentiation program in the GSCs. Depletion of TRF2 also sensitizes GSCs to temozolomide, a DNA-alkylating agent currently used to treat glioblastoma. Targeting TRF2 significantly increased the survival of mice bearing GSC xenografts. These findings reveal a role for TRF2 in the maintenance of REST-associated proliferation and chemotherapy resistance of GSCs, suggesting that TRF2 is a potential therapeutic target for glioblastoma.

KW - Cancer stem cells

KW - Glioblastoma

KW - Telomeres

KW - Transcriptional repression

UR - http://www.scopus.com/inward/record.url?scp=84906322141&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906322141&partnerID=8YFLogxK

U2 - 10.1002/glia.22708

DO - 10.1002/glia.22708

M3 - Article

C2 - 24909307

AN - SCOPUS:84906322141

VL - 62

SP - 1687

EP - 1698

JO - GLIA

JF - GLIA

SN - 0894-1491

IS - 10

ER -