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
Publication statusPublished - 2014
Externally publishedYes

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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