Trends in Cell Biology
ReviewREST: an oncogene or a tumor suppressor?
Section snippets
The opposing roles of REST
REST [also known as Neuron-Restrictive Silencing Factor (NRSF)] is a zinc finger domain-endowed repressor protein concentrated in the nucleus. The binding of REST to RE-1 – a specific regulatory sequence in its target genes – triggers gene repression and regulation of this repressive effect is critical during neural differentiation. In stem cells, REST is highly expressed. This expression drops rapidly in neural progenitors and is maintained at very low levels after differentiation. The low
Tumorigenesis: a complex, multifactorial process
Tumorigenesis is a complex process, governed by a cascade of genetic and epigenetic events. This complexity often requires a reductionist approach, focusing on the role of a particular factor in tumorigenesis in primary tumor cells or tumor cell lines. Such results are often new and interesting, but require caution in terms of extrapolating to the in vivo tumor environment. The fact that activation of a single mechanism is sufficient to affect proliferation of tumor cells in vitro does not
REST in neural tumors
In neural tumors, the role of REST is oncogenic. High REST, present in relevant percentages of these tumors, stimulates their proliferation and worsens prognosis. For at least three types of neural tumor, a mechanism has been proposed to explain how high REST results in high proliferation. In the following subsections, we discuss these tumor types and proposed mechanisms for REST dependence (Figure 1).
REST in epithelial carcinomas
In non-neural cells, including epithelia, REST expression is high and REST plays the role of tumor suppressor. In this section, we discuss four different mechanisms that have been proposed to translate decreased REST expression into increased cell proliferation and transformation. These tumorigenic mechanisms were first identified in one (or both) of two types of cancer: breast cancer (∼20% of which are REST dependent) and SCLCs (well known, very aggressive carcinomas that account for 15–20% of
Clinical perspectives
Progress of research on REST-dependent tumors, with identification of mechanisms that trigger and sustain their growth, has already offered new perspectives in terms of diagnostics, prognosis, and therapy. To date, there is only a single laboratory test proposed for the presurgical identification of low-REST carcinomas, which uses the appearance in peripheral blood of REST-regulated transcripts as biomarkers [46]. Other, similar tests could be developed in the near future. In terms of
Concluding remarks
The role of REST in cell proliferation has attracted increasing interest over the past several years and we expect this to continue in the near future. Its differing roles in neural and non-neural cells have been confirmed by laboratories active in the field and therefore appear firmly established. Although one might have expected the two roles to result from two distinct mechanisms, activated by either high or low levels of REST, in reality the differing effects of REST appear to occur via
References (67)
- et al.
The many faces of REST oversee epigenetic programming of neuronal genes
Curr. Opin. Neurobiol.
(2005) Cross-regulation between an alternative splice activator and a transcription repressor controls neurogenesis
Mol. Cell
(2011)RE-1 silencing transcription factor-4 (REST4) is neither a transcriptional repressor nor a de-repressor
Neurochem. Int.
(2002)Nontelomeric TRF2-REST interaction modulates neuronal gene silencing and fate of tumor and stem cells
Curr. Biol.
(2008)A genetic screen for candidate tumor suppressors identifies REST
Cell
(2005)Transcriptional regulation: cancer, neurons and the REST
Curr. Biol.
(2005)Deubiquitinase USP37 is activated by CDK2 to antagonize APC(CDH1) and promote S phase entry
Mol. Cell
(2011)miR-124a is frequently down-regulated in glioblastoma and is involved in migration and invasion
Eur. J. Cancer
(2011)Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells
J. Biol. Chem.
(2012)The canonical Wnt pathway directly regulates REST/NRSF expression in chick spinal cord
Biochem. Biophys. Res. Commun.
(2003)
Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro
Dev. Biol.
mTor signaling in growth control and disease
Cell
CDYL bridges REST and histone methyltransferase for gene repression and suppression of cellular transformation
Mol. Cell
Squelching glioblastoma stem cells by targeting REST for proteasomal degradation
Trends Neurosci.
Phase II study of maintenance sunitinib following irinotecan and carboplatin as first line treatment for patients with extensive stage small-cell lung cancer
Lung Cancer
Ubiquitynation and deubiquitynation of REST and its roles in cancer
FEBS Lett.
The transcriptional repressor REST/NRSF modulates hedgehog signaling
Dev. Biol.
Chromatin crosstalk in development and disease: lessons from REST
Nat. Rev. Genet.
Ischemic insults derepress the gene silencer REST in neurons destined to die
J. Neurosci.
Epigenetic modulation of seizure-induced neurogenesis and cognitive decline
J. Neurosci.
Nerve growth factor is a potent inducer of proliferation and neuronal differentiation for adult rat chromaffin cells in vitro
J. Neurosci.
β-Cell regeneration in human pancreas
Semin. Immunopathol.
Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron restrictive silencer factor, which can be functionally countered by REST-VP16
Mol. Cancer Ther.
Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation
Mol. Cell. Biol.
Retinoic acid induces REST degradation and neuronal differentiation by modulating the expression of SCFβ-TRCP in neuroblastoma cells
Cancer
A signaling loop of REST, TSC2 and β-catenin governs proliferation and function of PC12 neural cells
J. Cell Sci.
REST regulates oncogenic properties of glioblastoma stem cells
Stem Cells
REST controls self-renewal and tumorigenic competence of human glioblastoma cells
PLoS ONE
REST in good times and bad. Roles in tumor suppressor and oncogenic activities
Cell Cycle
Expression and functions of the repressor element 1 (RE-1)-silencing transcription factor (REST) in breast cancer
J. Cell. Biochem.
The transcription factor REST is lost in aggressive breast cancer
PLoS Genet.
Reduced expression of the neuron restrictive silencer factor permits transcription of glycine receptor α1 subunit in small cell lung cancer cells
Oncogene
Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer
Oncogene
Cited by (67)
The NRSF/REST transcription factor in hallmarks of cancer: From molecular mechanisms to clinical relevance
2023, BiochimieCitation Excerpt :In PC12 differentiated neuronal cells derived from a pheochromocytoma cell line, REST, TSC2, and β-catenin have been linked in a crucial feedback system for PC12 cell proliferation and neurosecretory functions (Fig. 3) [24,25]. In non-neuronal cells, REST is usually expressed at high levels and plays as a tumor suppressor; however, in epithelial carcinomas, mechanisms have been proposed that can explain the low levels of REST, leading to increased proliferation and cell transformation [65]. The REST-dependent mechanism in breast cancer is related to the dysregulation of the expression of two proteins: the chromodomain of protein Y (CDYL), a ubiquitous corepressor of REST, and LIN28A, an RNA-binding protein.
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2020, American Journal of Human GeneticsLong Non-coding RNA ITIH4-AS1 Accelerates the Proliferation and Metastasis of Colorectal Cancer by Activating JAK/STAT3 Signaling
2019, Molecular Therapy Nucleic AcidsKdm1a promotes SCLC progression by transcriptionally silencing the tumor suppressor Rest
2019, Biochemical and Biophysical Research CommunicationsEpigenetic regulation in medulloblastoma
2018, Molecular and Cellular NeuroscienceCitation Excerpt :REST represses gene expression by incorporating multiple epigenetic co-repressors such as H3K9 methyltransferase G9A, HDACs, and H3K4 demethylase KDM1A/LSD1 (Ballas and Mandel, 2005; Ooi and Wood, 2007). REST has been shown to function as a tumor suppressor in non-neural cancers and as an oncogene in neural tumors (Negrini et al., 2013). REST is highly expressed in medulloblastoma.