Dataset Information

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 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.

SUBMITTER: Zanotti S

PROVIDER: S-EPMC8280219 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Zanotti Sofia S Vanhauwaert Suzanne S Van Neste Christophe C Olexiouk Volodimir V Van Laere Jolien J Verschuuren Marlies M Van der Meulen Joni J Van der Meulen Joni J Mus Liselot M LM Durinck Kaat K Tilleman Laurentijn L Deforce Dieter D Van Nieuwerburgh Filip F Hogarty Michael D MD Decaesteker Bieke B De Vos Winnok H WH Speleman Frank F

Scientific reports 20210714 1

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 ...[more]

PMID: 34262099

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Dataset Information

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

Publications

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

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