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. 2009 Nov;32(11):559-65.
doi: 10.1016/j.tins.2009.07.005. Epub 2009 Sep 11.

Squelching glioblastoma stem cells by targeting REST for proteasomal degradation

Peisu Zhang  1 , Justin D Lathia, William A Flavahan, Jeremy N Rich, Mark P Mattson
Affiliations

Squelching glioblastoma stem cells by targeting REST for proteasomal degradation

Peisu Zhang et al. Trends Neurosci. 2009 Nov.

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.

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Figures

Figure 1
Figure 1. Protocol for the isolation of glioblastoma stem cells from surgical specimens
(a) Glioblastoma surgical specimens are disassociated into a single-cell suspension and separated by fluorescence activated cell sorting (FACS) using antibodies against markers for cancer stem cells. The conventional marker used in the example here is the cell surface antigen CD133, but no definitive marker exists and additional markers have been suggested including L1CAM, A2B5, and CD15 [–73]. CD133+ cells are self-renewing stem cells as indicated by their ability to form neurospheres in culture and tumors when grafted into the brains of immunodeficient mice; in contrast CD133− cells form neither neurospheres in culture nor tumors in vivo. (b) CD133+ cancer stem cells isolated from a glioblastoma that had been surgically removed from a patient are shown. The cells were immunostained using antibodies against REST (red) and TRF2 (green). The cells were also labeled with the DNA-binding dye DAPI (blue) and the lower image is a merged image of all three labels and shows that REST and TRF2 are often co-localized in nuclear foci (arrows).
Figure 2
Figure 2. Characteristics and fates of normal neural progenitor cells and cancer stem cells
Cancer stem cells within a brain tumor may arise from normal stem cells or neural progenitor cells that harbor mutations. Cancer stem cells within glioblastomas may be particularly resistant to cytotoxic therapies, and therefore are a source of cells for cancer recurrence. To meet the challenge of a cure for glioblastomas, new therapies that selectively suppress proliferation and/or kill cancer stem cells must be found.
Figure 3
Figure 3. Mechanisms by which TRF2 and SCFβ-TrCP regulate cancer stem cell fate via interactions with REST
REST is a transcriptional silencer that represses a large network of neural genes; this gene network is also intimately related to the regulatory repertoire of core pluripotency factors that control the self-renewal capacity of stem cells. (i) REST represses genes by binding to specific RE1 elements, and several proteins interact with REST to modify its activity including CoREST, histone deacetylase 2 (HDAC2) and telomere repeat-binding factor 2 (TRF2). The proteasomal degradation of REST is essential for de-repressing neural genes and neuronal differentiation. (ii) TRF2 binds to and stabilizes REST, thereby preventing its degradation, whereas activity of the ubiquitin E3 ligase SCFβ-TrCP accelerates proteasomal degradation of REST. (iii) TRF2 is also a critical component of the shelterin protein complex that protects and stabilizes telomeres. Gene therapies that deplete or neutralize TRF2 will therefore have a dual adverse effect on cancer stem cells by exposing telomere ends to induce a DNA damage response involving the proteins ATM and γH2AX which triggers cell cycle arrest and apoptosis, and by depleting REST to engage the neuronal cell differentiation program. Increased expression of SCFβ-TrCP would also deplete REST and inhibit cancer stem cell growth.
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References

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