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.

• Authors: Yun Bai, Justin D Lathia, Peisu Zhang, William Flavahan, Jeremy N Rich, Mark P Mattson
• Journal: Glia (Glia) Vol. 62 Issue 10 Pg. 1687-98 (Oct 2014) ISSN: 1098-1136 [Electronic] United States
• PMID: 24909307 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents, Alkylating
• Neural Cell Adhesion Molecule L1
• RE1-silencing transcription factor
• RNA, Messenger
• RNA, Small Interfering
• Repressor Proteins
• TERF2 protein, human
• TUBB3 protein, human
• Telomeric Repeat Binding Protein 2
• Tubulin
• Dacarbazine
• Temozolomide

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Brain Neoplasms (physiopathology, therapy)
• Carcinogenesis (drug effects, metabolism)
• Cell Differentiation (drug effects, physiology)
• Cell Line, Tumor
• Dacarbazine (analogs & derivatives, pharmacology)
• Genetic Vectors
• Glioblastoma (physiopathology, therapy)
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Targeted Therapy (methods)
• Neoplasm Transplantation
• Neoplastic Stem Cells (drug effects, physiology)
• Neural Cell Adhesion Molecule L1 (metabolism)
• RNA, Messenger (metabolism)
• RNA, Small Interfering
• Repressor Proteins (metabolism)
• Telomeric Repeat Binding Protein 2 (genetics, metabolism)
• Temozolomide
• Tubulin (metabolism)