Inhibitors of ribosome biogenesis repress the growth of MYCN-amplified neuroblastoma

Hald, Øyvind Holsbø; Olsen, Lotte; Gallo-Oller, Gabriel; Elfman, Lotta; Løkke, Cecilie; Kogner, Per; Sveinbjørnsson, Baldur; Flægstad, Trond; Johnsen, John Inge; Einvik, Christer

doi:10.1038/s41388-018-0611-7

Cited by 59 publications

(57 citation statements)

References 42 publications

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“…Finally, SOX11 repressed targets are enriched for gene sets involved in translation initiation, ribosome hyperactivity and mRNA processing, which is indicative of an enhanced ribosome biogenesis response as previously reported in MYCN driven NB 21 (Fig. 4c).…”

Section: The Sox11 Regulated Transcriptome Is Involved In Epigenetic supporting

confidence: 77%

SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma

Decaesteker

Louwagie

Loontiens

et al. 2020

Preprint

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The pediatric extra-cranial tumor neuroblastoma (NB) is characterised by a low mutation burden while copy number alterations are present in most high-risk cases. We identified SOX11 as a strong lineage dependency transcription factor in adrenergic NB based on recurrent chromosome 2p focal gains and amplifications, its specific expression in the normal sympatho-adrenal lineage and adrenergic NBs and its regulation by multiple adrenergic specific cis-interacting (super-)enhancers. Adrenergic NBs are strongly dependent on high SOX11 expression levels for growth and proliferation. Through genome-wide DNA-binding and transcriptome analysis, we identified and validated functional SOX11 target genes, several of which implicated in chromatin remodeling and epigenetic modification. SOX11 controls chromatin accessibility predominantly affecting distal adrenergic lineage-specific enhancers marked by binding sites of the adrenergic core regulatory circuitry. During normal sympathoblast differentiation we find expression of SOX11 prior to members of the adrenergic core regulatory circuitry. Given the broad control of SOX11 of multiple epigenetic regulatory complexes and its presumed pioneer factor function, we propose that adrenergic NB cells have co-opted the normal role of SOX11 as a crucial regulator of chromatin accessibility and cell identity.

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Section: The Sox11 Regulated Transcriptome Is Involved In Epigenetic supporting

confidence: 77%

SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma

Decaesteker

Louwagie

Loontiens

et al. 2020

Preprint

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“…Inhibition of E2F1 suppressed neuroblastoma progression [23]. Inhibition of ribosome singling pathway was also a promising strategy in neuroblastoma treatment [24]. However, the functions and prognosis of ARMC6, DCTPP1, EIF4G1, ELOVL6 and FBL in neuroblastoma were not reported.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of MYCN related genes in pediatric neuroblastoma: a study based on TARGET and GEO datasets

Wang

et al. 2020

BMC Pediatr

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Background: Neuroblastoma patients with MYCN amplification are associated with poor prognosis. However, the prognostic relevance of MYCN associated genes in neuroblastoma is unclear. Methods: The expression profiles of MYCN associated genes were identified from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) datasets. Enriched transcription factors and signaling pathways were determined using gene set enrichment analysis (GSEA). Kaplan-Meier plotter was used to identify the prognostic relevance of MYCN associated genes. Multivariate cox regression and Spearman's correlation were used to determine the correlation coefficients of MYCN associated genes. Results: In TARGET and GSE85047 datasets, neuroblastoma patients with MYCN amplification were associated with worse prognosis. Transcription factor MYC was positively associated with MYCN amplification in GSEA assay. We identified 13 MYC target genes which were increased in neuroblastoma patients with MYCN amplification in TARGET, GSE19274 and GSE85047 datasets. Moreover, six out of the 13 MYC target genes ARMC6, DCTPP1, EIF4G1, ELOVL6, FBL and PRMT1 were associated with adverse prognosis in TARGET and GSE85047 datasets. Transcription factor E2F1 was up-regulated by MYCN amplification and associated with the poor prognosis of neuroblastoma. Furthermore, RPS19 in ribosome signaling pathway was also associated with MYCN amplification and correlated with the poor prognosis of neuroblastoma. At last, we showed that most of MYCN target genes were correlated with each other. However, EIF4G1 was an independent prognostic marker. And the prognostic effects of the combination of MYCN amplification and EIF4G1 expression were more significant than MYCN or EIF4G1 alone. Conclusions: MYCN target genes ARMC6, DCTPP1, EIF4G1, ELOVL6, FBL, PRMT1, E2F1 and RPS19 had significant prognostic effects in pediatric neuroblastoma. And neuroblastoma patients without MYCN amplification and low EIF4G1 expression had best prognosis.

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“…In overview, these results indicate a clear and an almost complete breakdown of the ribosome and the spliceosome pathways, which consequently might explain the decrease of cell proliferation. It has been reported that repressing or perturbing the ribosome biogenesis decreases the growth of the cells [42], and/or even could drive cells into senescence [43].…”

Section: Discussionmentioning

confidence: 99%

jouvence, a new human H/ACA snoRNA involves in the control of cell proliferation and differentiation

El-Khoury

Bignon

Martin

2020

Preprint

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Small nucleolar RNAs (snoRNAs) are non-coding RNAs conserved from archeobacteria to mammals. In humans, various snoRNAs have been associated with pathologies as well as with cancer. Recently in Drosophila, a new snoRNA named jouvence has been involved in lifespan.Since snoRNAs are well conserved through evolution, both structurally and functionally, jouvence orthologue has been identified in human, allowing hypothesizing that jouvence could display a similar function (increasing healthy lifespan) in human. Here, we report the characterization of the human snoRNA-jouvence, which was not yet annotated in the genome.We show, both in stably cancerous cell lines and in primary cells, that its overexpression stimulates the cell proliferation. In contrast, its knockdown, by siRNA leads to an opposite phenotype, a decrease in cell proliferation. Transcriptomic analysis reveals that overexpression of jouvence leads to a dedifferentiation signature of the cells, a cellular effect comparable to rejuvenation. Inversely, the knockdown of jouvence leads to a decrease of genes involved in ribosomes biogenesis and spliceosome in agreement with the canonical role of a H/ACA box snoRNA. In this context, jouvence could represent a now tool to fight against the deleterious effect of aging, as well as a new target in cancer therapy.

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Inhibitors of ribosome biogenesis repress the growth of MYCN-amplified neuroblastoma

Cited by 59 publications

References 42 publications

SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma

SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma

Prognostic significance of MYCN related genes in pediatric neuroblastoma: a study based on TARGET and GEO datasets

jouvence, a new human H/ACA snoRNA involves in the control of cell proliferation and differentiation

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