REST: an oncogene or a tumor suppressor?

doi:10.1016/j.tcb.2013.01.006

Trends in Cell Biology

Volume 23, Issue 6, June 2013, Pages 289-295

https://doi.org/10.1016/j.tcb.2013.01.006 Get rights and content

The Repressor Element-1 (RE-1) Silencing Transcription (REST) factor, which is highly expressed in stem cells and non-neural cells, with low expression in neurons and other neural cells, orchestrates neural differentiation and preserves the unique neural phenotype. REST also plays a role in proliferation, although its effect differs depending on the cell type. It acts as an oncogene in neural cells and tumors (medulloblastomas, neuroblastomas, glioblastomas) and as a tumor suppressor in carcinomas of the lung, breast, and colon. The mechanisms underlying this duality have started to emerge recently and new therapeutic approaches based on these findings are being developed. Here, we present the mechanisms proposed to account for the oncogenic and antioncogenic roles of REST and discuss the therapeutic perspective of recent advances, particularly for small-cell lung cancer.

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

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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.
The RE-1 silencing transcription factor (REST), or neuron restrictive silencing factor (NRSF), was first identified as a repressor of neuronal genes in non-neuronal tissue. Interestingly, this transcription factor may act as a tumor suppressor or an oncogenic role in developing neuroendocrine and other tumors in patients. The hallmarks of cancer include six biological processes, including proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, inducing angiogenesis, and activating invasion and metastasis. In addition to two emerging hallmarks, the reprogramming of energy metabolism and evasion of the immune response are all implicated in the development of human tumors. It is essential to know the role of these processes as they will affect the outcome of alternatives for cancer treatment. Various studies in this review demonstrate that NRSF/REST affects the different hallmarks of cancer that could position NRSF/REST as an essential target in the therapy and diagnosis of certain types of cancer.
Ovarian Cancer Risk Variants Are Enriched in Histotype-Specific Enhancers and Disrupt Transcription Factor Binding Sites
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Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability ( $h_{g}^{2}$ ) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%–6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin.
Long Non-coding RNA ITIH4-AS1 Accelerates the Proliferation and Metastasis of Colorectal Cancer by Activating JAK/STAT3 Signaling
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Accumulating evidence has uncovered long non-coding RNAs (lncRNAs) as central regulators in the pathogenesis of diverse human cancers including colorectal cancer (CRC). The present study discovered that a novel lncRNA ITIH4 antisense RNA 1 (ITIH4-AS1) was frequently under-expressed in most normal human tissues, including colon tissues. Therefore, we aimed to investigate the role of ITIH4-AS1 in CRC. Interestingly, a significant overexpression of ITIH4-AS1 was observed in CRC cell lines relative to normal NCM460 cells. Also, we investigated the facilitating role of ITIH4-AS1 in CRC cell growth and metastasis both in vitro and in vivo. Additionally, we explained that ITIH4-AS1 upregulation in CRC was attributed to downregulation or even depletion of RE1 silencing transcription factor (REST), a presently identified transcriptional repressor for ITIH4-AS1. Meanwhile, the contribution of ITIH4-AS1 to CRC development was validated to rely on the activation of the JAK/STAT3 pathway. More importantly, we verified that FUS interacted with both ITIH4-AS1 and STAT3, and that ITIH4-AS1 evoked nuclear translocation of phosphorylated (p)-STAT3 in CRC through recruiting FUS. In summary, our findings unveiled for the first time that upregulation of ITIH4-AS1 induced by the downregulated REST exerts pro-tumor functions in CRC through FUS-dependent activation of the JAK/STAT3 pathway, implying that targeting ITIH4-AS1 may be a novel effective strategy for CRC therapy.
Kdm1a promotes SCLC progression by transcriptionally silencing the tumor suppressor Rest
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Small cell lung carcinoma (SCLC) is one of the deadliest cancer types, with a 5-year survival rate less than 10%. Kdm1a/Lsd1 has recently been implicated as a potential therapeutic target for SCLC. However, the underlying molecular mechanism by which Kdm1a promotes the oncogenesis of SCLC has not been fully understood. Kdm1a is significantly elevated in most human SCLC specimens, whereas Rest, a tumor suppressor and neuronal repressive transcriptional factor, is typically inactivated. Knock-out of Kdm1a (Kdm1a-KO) in mouse SCLC cell lines resulted in the suppression of cell growth and soft agar colony formation. RNA-Seq analysis of the Kdm1a-KO cells revealed significant repression of a program of neuroendocrine signature genes, and conversely, a significant upregulation of a network of genes capable of inhibiting tumor cell growth. Rest was identified among the top 10 upregulated genes in Kdm1a-KO cells. The treatment of the SCLC cells with Kdm1a demethylase inhibitors resulted in a dramatic up-regulation of Rest similar to the extent of that in Kdm1a-KO cells. Importantly, accompanying the restored expression of the SCLC signature genes, knock-out of Rest in Kdm1a-KO cells rescued the restricted cell growth and soft agar colony formation. Taken together, these novel findings show that Kdm1a is a key transcriptional repressor of Rest, and that suppression of SCLC progression by the targeted inhibition of Kdm1a depends on the reactivation of Rest, suggesting a new strategy for effective SCLC treatment by targeting the Kdm1a/Rest molecular pathway.
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Citation 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.
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Trends in Cell Biology

ReviewREST: an oncogene or a tumor suppressor?

Section snippets

The opposing roles of REST

Tumorigenesis: a complex, multifactorial process

REST in neural tumors

REST in epithelial carcinomas

Clinical perspectives

Concluding remarks

Curr. Opin. Neurobiol.

Mol. Cell

Neurochem. Int.

Curr. Biol.

Cell

Curr. Biol.

Mol. Cell

Eur. J. Cancer

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Dev. Biol.

Cell

Mol. Cell

Trends Neurosci.

Lung Cancer

FEBS Lett.

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

Review
REST: an oncogene or a tumor suppressor?

Retinoic acid induces REST degradation and neuronal differentiation by modulating the expression of SCF^β-TRCP in neuroblastoma cells