REST Controls Self-Renewal and Tumorigenic Competence of Human Glioblastoma Cells

Conti, Luciano; Crisafulli, Laura; Caldera, Valentina; Tortoreto, Monica; Brilli, Elisa; Conforti, Paola; Zunino, Franco; Magrassi, Lorenzo; Schiffer, Davide; Cattaneo, Elena

doi:10.1371/journal.pone.0038486

Cited by 90 publications

(109 citation statements)

References 42 publications

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“…For example, in human medulloblastoma tumors (13) and normal human brain tissue (26), NRSF/REST staining was observed to be localized to the nuclei. Conti et al (14) also reported that in gliomas, NRSF/REST exhibited a nuclear staining pattern (14). In the present study, positive NRSF/REST staining was detected in the nuclei and cytoplasm in normal liver tissue; whereas, in liver carcinoma, NRSF/REST was predominantly detected in the cytoplasm.…”

Section: Discussionsupporting

confidence: 61%

“…Similar results have been previously observed in other tissues. For example, Conti et al (14) also reported that in normal human tissue, NRSF/REST immunoreactivity was detected in the cytoplasm of selected neurons. Furthermore, Orta-Salazar et al (27) reported that in the hippocampus of a 3xTg-AD mouse (a mouse model of Alzheimer's disease), the nuclei and cytoplasm were NRSF/REST-positive.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Lawinger et al (11) reported that NRSF/REST levels were high in three types of human medulloblastoma cells. Furthermore, Fuller et al (13) reported that expression of NRSF/REST was increased in human medulloblastoma tumors compared with normal brain tissue samples (13) and Conti et al (14) observed that NRSF/REST expression was increased in human GBM. The present study demonstrated that the number of samples with high NRSF/REST expression was reduced in CCC compared with normal tissues, indicating that decreased NRSF/REST levels may be associated with the occurrence and/or poor prognosis of CCC.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have investigated the expression and, to a lesser extent, the function of NRSF/REST in tumors of the nervous system (8)(9)(10)(11)(12)(13)(14)(15). Certain tumors, including neuroblastoma, share a number of biological properties with neuronal progenitor cells and, thus, can acquire neuronal phenotypes in response to a variety of agents.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, high NRSF/REST levels have been detected in human medulloblastoma cell lines and tumors (11)(12)(13). Similarly, in human glioblastoma multiforme (GBM), NRSF/REST is highly expressed (14) and its inhibition suppresses the proliferation and migration of GBM cells (15).…”

Section: Introductionmentioning

confidence: 99%

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NRSF/REST levels are decreased in cholangiocellular carcinoma but not hepatocellular carcinoma compared with normal liver tissues: A tissue microarray study

Zhang

et al. 2018

Oncol Lett

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Abstract. The transcription factor neuron-restrictive silencer factor (NRSF), also termed repressor element 1-silencing transcription factor (REST), has been previously demonstrated to repress the expression of neuronal genes in non-neuronal cells, facilitating the controlled development and organization of nerve tissue. However, previous studies have reported NRSF/REST to be upregulated or downregulated in multiple types of carcinoma. Liver diseases are a major global health concern, with cirrhosis and liver carcinoma among the most common causes of mortality worldwide. A previous study demonstrated that there were >400 NRSF/REST target genes in mouse liver cells; however, the expression profile of NRSF/REST in human liver disease remains unclear. The present study examined NRSF/REST expression in human normal and liver carcinoma samples using tissue microarray immunohistochemistry. The results demonstrated that in normal liver tissues, NRSF/REST can be detected in the cytoplasm and nuclei of the cell; whereas in the liver carcinoma tissue, NRSF/REST is only detected in the cytoplasm. Furthermore, the number of samples with high levels of NRSF/REST was significantly lower in cholangiocellular carcinoma samples compared with normal tissues. Additionally, no detectable sex-or age-associated differences were identified in NRSF/REST expression among all the tissues examined. In conclusion, the results of the present study revealed nuclear loss of NRSF/REST in hepatic carcinomas and decreased expression of NRSF/REST in cholangiocellular carcinoma, indicating that the cytoplasmic translocation of NRSF/REST may be involved in liver tumorigenesis. A low expression level of NRSF/REST may be a novel biomarker for cholangiocellular carcinoma. IntroductionNeuron-restrictive silencer factor (NRSF), also termed repressor element 1-silencing transcription factor (REST), is a zinc-finger transcription factor and an important regulator of neural genes (1). Chong et al (2) first reported that NRSF/REST is a silencer protein that reduces the expression of sodium channel genes in neurons. A previous study demonstrated that NRSF/REST is an important regulator of neurogenesis in vitro and in vivo. For example, downregulation of NRSF/REST in embryonic stem cells induces neuronal lineage differentiation (3), and knockdown of NRSF/REST in cultured neural stem cells induces the expression of pro-neuronal genes, including neuronal differentiation 1, neuron-specific class III β-tubulin and doublecortin (4). In Xenopus and chicken embryos, NRSF/REST inactivation induces abnormal neurogenesis and inhibits the repression of neuronal tubulin and several other neuronal target genes (5,6). Additionally, NRSF/REST overexpression represses the expression of neuronal genes, including N-tubulin and neuronal cell adhesion molecule (7).Numerous studies have investigated the expression and, to a lesser extent, the function of NRSF/REST in tumors of the nervous system (8-15). Certain tumors, including neuroblastoma, share a number of biological propert...

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NRSF/REST levels are decreased in cholangiocellular carcinoma but not hepatocellular carcinoma compared with normal liver tissues: A tissue microarray study

Zhang

et al. 2018

Oncol Lett

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Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells

Bai

Lathia

Zhang

et al. 2014

Glia

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Glioblastoma is the most prevalent primary brain tumor and is essentially universally fatal within two years of diagnosis. Glioblastomas contain cellular hierarchies with self-renewing glioblastoma stem cells (GSCs) that are often resistant to chemotherapy and radiation therapy. GSCs express high amounts of repressor element 1 silencing transcription factor (REST), which may contribute to their resistance to standard therapies. Telomere repeat-binding factor 2 (TRF2) stablizes telomeres and REST to maintain self-renewal of neural stem cells and tumor cells. Here we show viral vector-mediated delivery of shRNAs targeting TRF2 mRNA depletes TRF2 and REST from GSCs isolated from patient specimens. As a result, GSC proliferation is reduced and the level of proteins normally expressed by postmitotic neurons (L1CAM and β3-tubulin) is increased, suggesting that loss of TRF2 engages a cell differentiation program in the GSCs. Depletion of TRF2 also sensitizes GSCs to temozolomide, a DNA-alkylating agent currently used to treat glioblastoma. Targeting TRF2 significantly increased the survival of mice bearing GSC xenografts. These findings reveal a role for TRF2 in the maintenance of REST-associated proliferation and chemotherapy resistance of GSCs, suggesting that TRF2 is a potential therapeutic target for glioblastoma.

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Extracellular signal‐related kinase 2/specificity protein 1/specificity protein 3/repressor element‐1 silencing transcription factor pathway is involved in Aroclor 1254‐induced toxicity in SH‐SY5Y neuronal cells

Formisano

Guida

Laudati

et al. 2014

J of Neuroscience Research

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Polychlorinated biphenyls (PCBs) cause a wide spectrum of toxic effects in the brain through undefined mechanisms. Exposure to the PCB mixture Aroclor-1254 (A1254) increases the repressor element-1 silencing transcription factor (REST) expression, leading to neuronal death. This study sought to understand the sequence of some molecular mechanisms to determine whether A1254 could increase REST expression and the cytoprotective effect of the phorbol ester tetradecanoylphorbol acetate (TPA) on A1254-induced toxicity in SH-SY5Y cells. As shown by Western blot analysis, A1254 (10 µg/ml) downregulates extracellular signal-related kinase 2 (ERK2) phosphorylation in a time-dependent manner, thereby triggering the binding of specificity protein 1 (Sp1) and Sp3 to the REST gene promoter as revealed by chromatin immunoprecipitation analysis. This chain of events results in an increase in REST mRNA and cell death, as assessed by quantitative real-time polymerase chain reaction and dimethylthiazolyl-2-5-diphenyltetrazolium-bromide assay, respectively. Accordingly, TPA prevented both the A1254-induced decrease in ERK2 phosphorylation and the A1254-induced increase in Sp1, Sp3, and REST protein expression. After 48 hr, TPA prevented A1254-induced cell death. ERK2 overexpression counteracted the A1254-induced increase in Sp1 and Sp3 protein expression and prevented A1254-induced Sp1 and Sp3 binding to the REST gene promoter, thus counteracting the increase in REST mRNA expression induced by the toxicant. In neuroblastoma SH-SY5Y cells, ERK2/Sp1/SP3/REST is a new pathway underlying the neurotoxic effect of PCB. The ERK2/Sp1/Sp3/REST pathway, which underlies A1254-induced neuronal death, might represent a new drug signaling cascade in PCB-induced neuronal toxicity.

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REST Controls Self-Renewal and Tumorigenic Competence of Human Glioblastoma Cells

Cited by 90 publications

References 42 publications

NRSF/REST levels are decreased in cholangiocellular carcinoma but not hepatocellular carcinoma compared with normal liver tissues: A tissue microarray study

NRSF/REST levels are decreased in cholangiocellular carcinoma but not hepatocellular carcinoma compared with normal liver tissues: A tissue microarray study

Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells

Extracellular signal‐related kinase 2/specificity protein 1/specificity protein 3/repressor element‐1 silencing transcription factor pathway is involved in Aroclor 1254‐induced toxicity in SH‐SY5Y neuronal cells

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