Squelching glioblastoma stem cells by targeting REST for proteasomal degradation
Peisu Zhang1, Justin D Lathia, William A Flavahan
1Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA. zhangpe@grc.nia.nih.gov
Abstract:
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.
Insights
Glioblastoma stem cells drive tumor recurrence. New research reveals REST protein stability is key, with TRF2 and SCFbeta-TrCP regulating its degradation to inhibit cancer stem cell self-renewal.
Area of Science:
- Neuroscience
- Cancer Biology
- Epigenetics
Background:
- Glioblastoma stem cells (GSCs) are resistant to conventional therapies, leading to tumor recurrence.
- Understanding GSC self-renewal mechanisms is crucial for developing targeted therapies.
- The transcriptional repressor REST is implicated in neural progenitor cell fate and potentially GSC self-renewal.
Purpose of the Study:
- To investigate the epigenetic mechanisms controlling glioblastoma stem cell self-renewal.
- To identify novel therapeutic targets for glioblastoma treatment.
Main Methods:
- Investigated the role of the transcriptional repressor REST in glioblastoma stem cell self-renewal.
- Examined the regulatory mechanisms controlling REST stability, focusing on TRF2 and SCFbeta-TrCP.
- Assessed the impact of modulating REST stability on cancer stem cell proliferation.
Main Results:
- Two novel mechanisms regulating REST stability were identified: TRF2 binding and SCFbeta-TrCP activity.
- Reduced TRF2 binding and increased SCFbeta-TrCP activity lead to REST proteasomal degradation.
- Inhibition of REST degradation suppressed glioblastoma stem cell proliferation.
Conclusions:
- REST stability, regulated by TRF2 and SCFbeta-TrCP, is a critical factor in glioblastoma stem cell self-renewal.
- Targeting REST degradation presents a potential therapeutic strategy for glioblastoma.
- Therapies targeting REST and TRF2 may have fewer neurological side effects than conventional treatments.
