Squelching glioblastoma stem cells by targeting REST for proteasomal degradation.
Glioblastoma brain tumors harbor a small population of cancer stem cells that are resistant to conventional chemotherapeutic and radiation treatments, and are believed responsible for tumor recurrence and mortality. The identification of the epigenetic molecular mechanisms that control self-renewal of glioblastoma stem cells will foster development of targeted therapeutic approaches. The transcriptional repressor REST, best known for its role in controlling cell fate decisions in neural progenitor cells, may also be crucial for cancer stem cell self-renewal. Two novel mechanisms for regulating the stability of REST have recently been revealed: these involve the telomere-binding protein TRF2 and the ubiquitin E3 ligase SCFbeta-TrCP. Reduced TRF2 binding to REST, and increased SCFbeta-TrCP activity, target REST for proteasomal degradation and thereby inhibit cancer stem cell proliferation. Neurological side effects of treatments that target REST and TRF2 may be less severe than conventional brain tumor treatments because postmitotic neurons do not express REST and have relatively stable telomeres.
Zhang
Peisu
P
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA. zhangpe@grc.nia.nih.gov
Lathia
Justin D
JD
Flavahan
William A
WA
Rich
Jeremy N
JN
Mattson
Mark P
MP
D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012097:Repressor Proteins / Q000187:drug effects / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099229:RE1-Silencing Transcription Factor
D012097:Repressor Proteins; D044843:SKP Cullin F-Box Protein Ligases; D035341:Telomeric Repeat Binding Protein 2; D000099229:RE1-Silencing Transcription Factor