MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells

Abstract MYCN is an oncogenic driver in neural crest-derived neuroblastoma and medulloblastoma. To better understand the early effects of MYCN activation in a neural-crest lineage context, we profiled the transcriptome of immortalized human retina pigment epithelial cells with inducible MYCN activat...

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Autores principales:	Sofia Zanotti, Suzanne Vanhauwaert, Christophe Van Neste, Volodimir Olexiouk, Jolien Van Laere, Marlies Verschuuren, Joni Van der Meulen, Liselot M. Mus, Kaat Durinck, Laurentijn Tilleman, Dieter Deforce, Filip Van Nieuwerburgh, Michael D. Hogarty, Bieke Decaesteker, Winnok H. De Vos, Frank Speleman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/867372e4c7ba46fb8fbf180861fa84ee
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spelling	oai:doaj.org-article:867372e4c7ba46fb8fbf180861fa84ee2021-12-02T16:14:17ZMYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells10.1038/s41598-021-93863-92045-2322https://doaj.org/article/867372e4c7ba46fb8fbf180861fa84ee2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93863-9https://doaj.org/toc/2045-2322Abstract MYCN is an oncogenic driver in neural crest-derived neuroblastoma and medulloblastoma. To better understand the early effects of MYCN activation in a neural-crest lineage context, we profiled the transcriptome of immortalized human retina pigment epithelial cells with inducible MYCN activation. Gene signatures associated with elevated MYC/MYCN activity were induced after 24 h of MYCN activation, which attenuated but sustained at later time points. Unexpectedly, MYCN activation was accompanied by reduced cell growth. Gene set enrichment analysis revealed a senescence-like signature with strong induction of p53 and p21 but in the absence of canonical hallmarks of senescence such as β-galactosidase positivity, suggesting incomplete cell fate commitment. When scrutinizing the putative drivers of this growth attenuation, differential gene expression analysis identified several regulators of nucleolar stress. This process was also reflected by phenotypic correlates such as cytoplasmic granule accrual and nucleolar coalescence. Hence, we propose that the induction of MYCN congests the translational machinery, causing nucleolar stress and driving cells into a transient pre-senescent state. Our findings shed new light on the early events induced by MYCN activation and may help unravelling which factors are required for cells to tolerate unscheduled MYCN overexpression during early malignant transformation.Sofia ZanottiSuzanne VanhauwaertChristophe Van NesteVolodimir OlexioukJolien Van LaereMarlies VerschuurenJoni Van der MeulenLiselot M. MusKaat DurinckLaurentijn TillemanDieter DeforceFilip Van NieuwerburghMichael D. HogartyBieke DecaestekerWinnok H. De VosFrank SpelemanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sofia Zanotti Suzanne Vanhauwaert Christophe Van Neste Volodimir Olexiouk Jolien Van Laere Marlies Verschuuren Joni Van der Meulen Liselot M. Mus Kaat Durinck Laurentijn Tilleman Dieter Deforce Filip Van Nieuwerburgh Michael D. Hogarty Bieke Decaesteker Winnok H. De Vos Frank Speleman MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells
description	Abstract MYCN is an oncogenic driver in neural crest-derived neuroblastoma and medulloblastoma. To better understand the early effects of MYCN activation in a neural-crest lineage context, we profiled the transcriptome of immortalized human retina pigment epithelial cells with inducible MYCN activation. Gene signatures associated with elevated MYC/MYCN activity were induced after 24 h of MYCN activation, which attenuated but sustained at later time points. Unexpectedly, MYCN activation was accompanied by reduced cell growth. Gene set enrichment analysis revealed a senescence-like signature with strong induction of p53 and p21 but in the absence of canonical hallmarks of senescence such as β-galactosidase positivity, suggesting incomplete cell fate commitment. When scrutinizing the putative drivers of this growth attenuation, differential gene expression analysis identified several regulators of nucleolar stress. This process was also reflected by phenotypic correlates such as cytoplasmic granule accrual and nucleolar coalescence. Hence, we propose that the induction of MYCN congests the translational machinery, causing nucleolar stress and driving cells into a transient pre-senescent state. Our findings shed new light on the early events induced by MYCN activation and may help unravelling which factors are required for cells to tolerate unscheduled MYCN overexpression during early malignant transformation.
format	article
author	Sofia Zanotti Suzanne Vanhauwaert Christophe Van Neste Volodimir Olexiouk Jolien Van Laere Marlies Verschuuren Joni Van der Meulen Liselot M. Mus Kaat Durinck Laurentijn Tilleman Dieter Deforce Filip Van Nieuwerburgh Michael D. Hogarty Bieke Decaesteker Winnok H. De Vos Frank Speleman
author_facet	Sofia Zanotti Suzanne Vanhauwaert Christophe Van Neste Volodimir Olexiouk Jolien Van Laere Marlies Verschuuren Joni Van der Meulen Liselot M. Mus Kaat Durinck Laurentijn Tilleman Dieter Deforce Filip Van Nieuwerburgh Michael D. Hogarty Bieke Decaesteker Winnok H. De Vos Frank Speleman
author_sort	Sofia Zanotti
title	MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells
title_short	MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells
title_full	MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells
title_fullStr	MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells
title_full_unstemmed	MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells
title_sort	mycn-induced nucleolar stress drives an early senescence-like transcriptional program in htert-immortalized rpe cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/867372e4c7ba46fb8fbf180861fa84ee
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MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells

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