p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity

Adriaens, Carmen; Standaert, Laura; Barra, Jasmine; Latil, Mathilde; Verfaillie, Annelien; Kalev, Peter; Boeckx, Bram; Wijnhoven, Paul W.G.; Radælli, Enrico; Vermi, William; Leucci, Eleonora; Lapouge, Gaëlle; Beck, Benjamin; Oord, Joost van den; Nakagawa, Shinichi; Hirose, Tetsuro; Sablina, Anna; Lambrechts, Diether; Aerts, Stein; Blanpain, Cédric; Marine, Jean–Christophe

doi:10.1038/nm.4135

Cited by 399 publications

(455 citation statements)

References 63 publications

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“…Until this point the only way to dissect these two isoforms was to transiently ablate NEAT1_2 with siRNA or ASOs, leaving NEAT1_1 intact (Sunwoo et al 2009;Imamura et al 2014;Adriaens et al 2016). To make a permanent NEAT1_2 knockout line, here we applied a variation on the YFP knock-in strategy used for promoter disruption: We targeted the genomic region closely downstream from the polyadenylation signal of the NEAT1_1 isoform to selectively disrupt NEAT1_2, leaving NEAT1_1 intact ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…NEAT1 transcription can be significantly influenced by p53 and is often up-regulated by stresses, such as hypoxia, viral infection/products, and genotoxic agents (Saha et al 2006;Choudhry et al 2014;Imamura et al 2014;Adriaens et al 2016). Unsurprisingly, there is also a strong link between high NEAT1 expression and more aggressive forms of cancer (Chakravarty et al 2014;Chai et al 2016;Chen et al 2016;Fu et al 2016;Ma et al 2016;Sun et al 2016;Wang et al 2016).…”

Section: Introductionmentioning

confidence: 99%

“…The shorter NEAT1_1 isoform, albeit highly abundant, is not sufficient for paraspeckle formation and its involvement with the function of paraspeckles is still unclear (Mao et al 2011). Moreover, several functional studies reported that overexpression of NEAT1_1 may promote tumor growth and metastasis (Chakravarty et al 2014;Chen et al 2016;Sun et al 2016), and other studies in different cancer subtypes have indicated that high NEAT1_2 expression is linked to worse cancer prognosis via the activation of ATR (ataxia telangiectasia and Rad3-related) pathways (Adriaens et al 2016). These reports seem to imply that the two NEAT1 isoforms may be functionally distinct, or even opposite, entities, thus rendering the relationship between the two NEAT1 isoforms and paraspeckles enigmatic.…”

Section: Introductionmentioning

confidence: 99%

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Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles

Harvey

Hodgetts

et al. 2017

RNA

124

113

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Large numbers of long noncoding RNAs have been discovered in recent years, but only a few have been characterized. NEAT1 (nuclear paraspeckle assembly transcript 1) is a mammalian long noncoding RNA that is important for the reproductive physiology of mice, cancer development, and the formation of subnuclear bodies termed paraspeckles. The two major isoforms of NEAT1 (3.7 kb NEAT1_1 and 23 kb NEAT1_2 in human) are generated from a common promoter and are produced through the use of alternative transcription termination sites. This gene structure has made the functional relationship between the two isoforms difficult to dissect. Here we used CRISPR-Cas9 genome editing to create several different cell lines: total NEAT1 knockout cells, cells that only express the short form NEAT1_1, and cells with twofold more NEAT1_2. Using these reagents, we obtained evidence that NEAT1_1 is not a major component of paraspeckles. In addition, our data suggest NEAT1_1 localizes in numerous nonparaspeckle foci we termed "microspeckles," which may carry paraspeckle-independent functions. This study highlights the complexity of lncRNA and showcases how genome editing tools are useful in dissecting the structural and functional roles of overlapping transcripts.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles

Harvey

Hodgetts

et al. 2017

RNA

124

113

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“…Both NEAT1_1 and NEAT1_2 are induced in an anoxic environment (10). A recent study reports that p53 induces the formation of NEAT1 lncRNA-containing paraspeckles that modulate the replication stress response and chemosensitivity (11). NEAT1 is also a p53-dependent lncRNA in chronic lymphocytic leukemia (12).…”

Section: Introductionmentioning

confidence: 99%

Long Noncoding RNA NEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/β-Catenin Pathway by Scaffolding EZH2

Chen

Cai

Wang³

et al. 2018

Clinical Cancer Research

291

240

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Purpose: Long noncoding RNAs have been implicated in gliomagenesis, but their mechanisms of action are mainly undocumented. Through public glioma mRNA expression data sets, we found that NEAT1 was a potential oncogene. We systematically analyzed the clinical significance and mechanism of NEAT1 in glioblastoma.Experimental Design: Initially, we evaluated whether NEAT1 expression levels could be regulated by EGFR pathway activity. We subsequently evaluated the effect of NEAT1 on the WNT/ b-catenin pathway and its target binding gene. The animal model supported the experimental findings.Results: We found that NEAT1 levels were regulated by EGFR pathway activity, which was mediated by STAT3 and NFkB (p65) downstream of the EGFR pathway. Moreover, we found that NEAT1 was critical for glioma cell growth and invasion by increasing b-catenin nuclear transport and downregulating ICAT, GSK3B, and Axin2. Taken together, we found that NEAT1 could bind to EZH2 and mediate the trimethylation of H3K27 in their promoters. NEAT1 depletion also inhibited GBM cell growth and invasion in the intracranial animal model.Conclusions: The EGFR/NEAT1/EZH2/b-catenin axis serves as a critical effector of tumorigenesis and progression, suggesting new therapeutic directions in glioblastoma. Clin Cancer Res; 1-12.Ó2017 AACR.

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“…As we known, TP53 is involved in many important cellular responses, such as apoptotic cell death, cell cycle arrest, and DNA repair. A recent study reported that TP53 induced formation of NEAT1 lncRNA‐containing paraspeckles that modulated the replication stress response and chemosensitivity (Adriaens et al ., 2016). Consistent with this report, TP53 mutation triggered down‐regulation of NEAT1 expression and resulted in poor response to tamoxifen (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

Zhang

Zhou

et al. 2018

Molecular Oncology

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Differences in individual drug responses are an obstacle to progression in cancer treatment, and predicting responses would help to plan treatment. The accumulation of cancer molecular profiling and drug response data provides opportunities and challenges to identify novel molecular signatures and mechanisms of tumor responsiveness to drugs. This study evaluated drug responses with a competing endogenous RNA (ceRNA) system that depended on competition between diverse RNA species. We identified drug response‐related ceRNA (DRCEs) by combining the sequence and expression data of long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA), and the survival data of cancer patients treated with drugs. We constructed a patient–drug two‐layer integrated network and used a linear weighting method to predict individual drug responses. DRCEs were found to be significantly enriched in known cancer and drug‐associated data resources, involved in biological processes known to mediate drug responses, and correlated to drug activity in cancer cell lines. The dysregulation of DRCE expression influenced drug response‐associated functions and pathways, suggesting DRCEs as potential therapeutic targets affecting drug responses. A further case study in breast invasive carcinoma (BRCA) found that DRCE expression was consistent with the drug response pattern and the aberrant expression of the two NEAT1‐related DRCEs may lead to poor response to tamoxifen therapy for patients with TP53 mutations. In summary, this study provides a framework for ceRNA‐based evaluation of clinical drug responses across multiple cancer types. Understanding the underlying molecular mechanisms of drug responses will allow improved response to chemotherapy and outcomes of cancer treatment.

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p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity

Cited by 399 publications

References 63 publications

Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles

Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles

Long Noncoding RNA NEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/β-Catenin Pathway by Scaffolding EZH2

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

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