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.
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China; Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland.
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.forename: Peisu
authors.initials: P
authors.lastname: Zhang
authors.forename: William
authors.initials: W
authors.lastname: Flavahan
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001932:Brain Neoplasms / Q000503:physiopathology / Q000628:therapy*; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D005822:Genetic Vectors; D005909:Glioblastoma / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D000077204:Temozolomide; D014404:Tubulin / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D039842:Neural Cell Adhesion Molecule L1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D035341:Telomeric Repeat Binding Protein 2; D000077204:Temozolomide; D014404:Tubulin; D000099229:RE1-Silencing Transcription Factor; C504753:TERF2 protein, human; C498585:TUBB3 protein, human
keywords: cancer stem cells; glioblastoma; telomeres; transcriptional repression