Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis

Mondal, Tanmoy; Juvvuna, Prasanna Kumar; Kirkeby, Agnete; Mitra, Sanhita; Kosalai, Subazini Thankaswamy; Traxler, Larissa; Hertwig, Falk; Wernig-Zorc, Sara; Miranda, Caroline; Deland, Lily; Volland, Ruth; Bartenhagen, Christoph; Bartsch, Deniz; Bandaru, Sashidhar; Engesser, Anne; Subhash, Santhilal; Martinsson, Tommy; Carén, Helena; Akyürek, Levent M.; Kurian, Leo; Kanduri, Meena; Huarte, Maite; Kogner, Per; Fischer, Matthias; Kanduri, Chandrasekhar

doi:10.1016/j.ccell.2018.01.020

Cited by 116 publications

(99 citation statements)

References 52 publications

(66 reference statements)

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“…Aberrant expressions of lncRNAs have been revealed in various pathological status, particular in cancers . Furthermore, lncRNAs also play important roles in various pathophysiological processes, including cancers . In NSCLC, several lncRNAs are reported to participate in tumourigenesis and/or development of NSCLC.…”

Section: Introductionmentioning

confidence: 99%

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A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

Lin

Yang

et al. 2018

J Cellular Molecular Medi

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Accumulating evidences revealed that long noncoding RNAs (lncRNAs) are frequently implicated in non‐small cell lung cancer (NSCLC). Herein, we reported the identification of a novel NSCLC‐associated functional lncRNA ZNF205 antisense RNA 1 (ZNF205‐AS1). ZNF205‐AS1 was increased in NSCLC tissues and cell lines, and associated with poor prognosis of NSCLC patients. Bioinformatics prediction, combined with experimental verification revealed that early growth response 4 (EGR4) directly bound to ZNF205‐AS1 promoter, increased the promoter activity of ZNF205‐AS1, and activated ZNF205‐AS1 transcription. Intriguingly, ZNF205‐AS1 transcript directly interacted with EGR4 mRNA, increased EGR4 mRNA stability, and up‐regulated EGR4 expression via RNA‐RNA interaction. Thus, ZNF205‐AS1 and EGR4 formed a positive feedback loop. Through regulating EGR4, ZNF205‐AS1 activated its own promoter activity. EGR4 was also increased in NSCLC and the expression of ZNF205‐AS1 was significantly positively correlated with EGR4 in NSCLC tissues. Gain‐of‐function and loss‐of‐function assays demonstrated that both ZNF205‐AS1 and EGR4 promoted NSCLC cell growth in vitro and NSCLC tumour growth in vivo. Concurrently depleting ZNF205‐AS1 and EGR4 more significantly repressed NSCLC tumour growth in vivo. Collectively, our study demonstrated that the positive feedback loop between ZNF205‐AS1 and EGR4 promotes NSCLC growth, and implied that targeting this feedback loop may be promising therapeutic strategy for NSCLC.

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Section: Introductionmentioning

confidence: 99%

“…[10][11][12][13] Furthermore, lncRNAs also play important roles in various pathophysiological processes, including cancers. [14][15][16][17][18] In NSCLC, several lncRNAs are reported to participate in tumourigenesis and/or development of NSCLC. LncRNA MALAT-1 is frequently revelated to regulate NSCLC metastasis.…”

mentioning

confidence: 99%

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

Lin

Yang

et al. 2018

J Cellular Molecular Medi

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“…Other factors, which also contribute to neuroblastoma tumorigenesis, are loss of heterozygosity (LOH) for chromosome 14 (14q), loss of NF1 and CDKN2A, amplification of DDX1 and MDM2, aberrant expression of neurotrophin receptors, ganglioside GD2, polycomb complex protein Bmi-1, micro RNAs (miR-10b, miR-29a/b, miR-335), as well as mutations in PHOX2B, ATRX, CHEK2 and BARD1 (53,(69)(70)(71)(72)(73)(74)(75)(76)(77). In addition to protein coding genes, long noncoding RNAs, such as neuroblastoma associated transcript-1 (NBAT-1) and Cancer Susceptibility 15 (CASC15), regulate neuroblastoma tumorigenesis via cell proliferation and neuronal differentiation (78,79).…”

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confidence: 99%

Targeting anaplastic lymphoma kinase in neuroblastoma

Umapathy

Mendoza-García

Hållberg

et al. 2019

APMIS

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Over the last decade, anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase (RTK), has been identified as a fusion partner in a diverse variety of translocation events resulting in oncogenic signaling in many different cancer types. In tumors where the full‐length ALK RTK itself is mutated, such as neuroblastoma, the picture regarding the role of ALK as an oncogenic driver is less clear. Neuroblastoma is a complex and heterogeneous tumor that arises from the neural crest derived peripheral nervous system. Although high‐risk neuroblastoma is rare, it often relapses and becomes refractory to treatment. Thus, neuroblastoma accounts for 10–15% of all childhood cancer deaths. Since most cases are in children under the age of 2, understanding the role and regulation of ALK during neural crest development is an important goal in addressing neuroblastoma tumorigenesis. An impressive array of tyrosine kinase inhibitors (TKIs) that act to inhibit ALK have been FDA approved for use in ALK‐driven cancers. ALK TKIs bind differently within the ATP‐binding pocket of the ALK kinase domain and have been associated with different resistance mutations within ALK itself that arise in response to therapeutic use, particularly in ALK‐fusion positive non‐small cell lung cancer (NSCLC). This patient population has highlighted the importance of considering the relevant ALK TKI to be used for a given ALK mutant variant. In this review, we discuss ALK in neuroblastoma, as well as the use of ALK TKIs and other strategies to inhibit tumor growth. Current efforts combining novel approaches and increasing our understanding of the oncogenic role of ALK in neuroblastoma are aimed at improving the efficacy of ALK TKIs as precision medicine options in the clinic.

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“…In mouse induced pluripotent stem cell models, HNF4A and MYC were both predicted as upstream regulators of genes involved in neuronal differentiation (Ando, Kato et al, 2015). Additionally, if validated in NB that HNF4α binds with both USP36 and SOX9 (Odom, Zizlsperger et al, 2004, Rouillard et al, 2016, HNF4α may have a direct impact on the core CASC14/15-USP36/CHD7-SOX9 pathway of NB suppression (Mondal et al, 2018). In this amplifier model, the weak but essential perturbations caused by suggestive genic variants or abnormal TF activity can be amplified by CTS and configure the complex and dynamic HNF4α-regulation.…”

Section: Hnf4a Presents As a Master Regulator Of Neuroblastoma Ctsmentioning

confidence: 96%

“…Querying these 151 NB-associated TADs with both identified CTSs allowed for pinpointing nine TAD regions with susceptible SNPs and CTS transcripts. One notable finding was gene DCDC2, whose copy number gain presented in 6 out of 29 NB tumors studied (Costa & Seuanez, 2018) and lies adjacent to NB suppressive lincRNA pairs CASC14/15 (Mondal, Juvvuna et al, 2018) (Table 1). Strong evidence also exists of DCDC2 interacting with both the CASC14/15 locus and the neuron-differentiate marker gene NRSN1 which comes from Hi-C mapping in the NB cell ( Figure EV3a).…”

Section: Clinical Relevance Of the Identified Neuroblastoma Ctssmentioning

confidence: 99%

Tipping-point analysis uncovers critical transition signals from gene expression profiles

Yang

Wang

Goldstein

et al. 2019

Preprint

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Highlights: We adopt 'tipping-point' theory to identify distribution-transition in disease regulatory states  Critical transcriptional transition happens between low-risk and a high-risk neuroblastoma states  A critical transition signal (CTS) based on coherent expression of genes and lncRNAs shows prognostic significance  GWAS-scans with the CTS unveiled five overlooked genes and four lncRNAs with promising clinical implications  We propose a CTS-amplifier model that unveils complex but mastering transregulation in disease AbstractTipping-point models have had success identifying transcriptional critical-transition signal (CTS) in tumor phenotypes using time-course data. Can these mathematical models be adopted to cross-sectional transcriptome profiles? Furthermore, can the 2 CTS analysis that characterizes tumor progression be applied to lncRNA-expression patterns? This study introduces a novel network-perturbation signature (NPS) scoring scheme to model a phenotype-defined tumor regulatory system. Applying NPS to neuroblastoma transcriptome of two patient populations yielded two CTSs that reproducibly identified a critical system transition between the low-risk and a high-risk state. The coherent expression pattern of one specific CTS, consisting of mRNA and lncRNA components, showed prognostic significance. Associating GWAS-scans with the CTS unveiled four overlooked intergenic loci and five genes with promising clinical significance. Additionally, a new mechanism of 'CTS-amplifier' is proposed, modeling how CTS-transcript fluctuation response to complex master regulators such as c-MYC and HNF4A uniquely in the transition state. Overall, NPS is a powerful computational approach that provides a breakthrough in phenomenological analysis of collective regulatory trajectory by applying 'tipping-point' theory to '-omics' data.

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Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis

Cited by 116 publications

References 52 publications

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

Targeting anaplastic lymphoma kinase in neuroblastoma

Tipping-point analysis uncovers critical transition signals from gene expression profiles

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