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Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells
Author(s) -
Bai Yun,
Lathia Justin D.,
Zhang Peisu,
Flavahan William,
Rich Jeremy N.,
Mattson Mark P.
Publication year - 2014
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22708
Subject(s) - biology , stem cell , cancer research , temozolomide , telomere , carcinogenesis , neural stem cell , transcription factor , cell growth , gene silencing , repressor , glioma , microbiology and biotechnology , cancer , genetics , gene
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. GLIA 2014;62:1687–1698