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

Sci Rep. 2021 Jul 14;11(1):14454. doi: 10.1038/s41598-021-93863-9.

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.

MeSH terms

  • Cell Line
  • Cell Nucleolus* / metabolism
  • Cell Proliferation
  • Cellular Senescence* / genetics
  • Humans
  • N-Myc Proto-Oncogene Protein* / genetics
  • N-Myc Proto-Oncogene Protein* / metabolism
  • Retinal Pigment Epithelium* / metabolism
  • Retinal Pigment Epithelium* / pathology
  • Stress, Physiological / genetics
  • Telomerase* / genetics
  • Telomerase* / metabolism
  • Transcriptome

Substances

  • N-Myc Proto-Oncogene Protein
  • MYCN protein, human
  • Telomerase
  • TERT protein, human