The long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype

Marta Montes*, Michal Lubas, Frederic S. Arendrup, Bettina Mentz, Neha Rohatgi, Sarunas Tumas, Lea M. Harder, Anders J. Skanderup, Jens S. Andersen, Anders H. Lund

*Corresponding author for this work

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Abstract

Oncogene-induced senescence provides a barrier against malignant transformation. However, it can also promote cancer through the secretion of a plethora of factors released by senescent cells, called the senescence associated secretory phenotype (SASP). We have previously shown that in proliferating cells, nuclear lncRNA MIR31HG inhibits p16/CDKN2A expression through interaction with polycomb repressor complexes and that during BRAF-induced senescence, MIR31HG is overexpressed and translocates to the cytoplasm. Here, we show that MIR31HG regulates the expression and secretion of a subset of SASP components during BRAF-induced senescence. The SASP secreted from senescent cells depleted for MIR31HG fails to induce paracrine invasion without affecting the growth inhibitory effect. Mechanistically, MIR31HG interacts with YBX1 facilitating its phosphorylation at serine 102 (p-YBX1S102) by the kinase RSK. p-YBX1S102 induces IL1A translation which activates the transcription of the other SASP mRNAs. Our results suggest a dual role for MIR31HG in senescence depending on its localization and points to the lncRNA as a potential therapeutic target in the treatment of senescence-related pathologies.

Original languageEnglish
Article number2459
JournalNature Communications
Volume12
Issue number1
Number of pages17
ISSN2041-1723
DOIs
Publication statusPublished - Dec 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Aging/genetics
  • Cell Line
  • Cell Proliferation/genetics
  • Cell Transformation, Neoplastic/genetics
  • Cellular Senescence/genetics
  • Cyclin-Dependent Kinase Inhibitor p16/biosynthesis
  • Gene Expression Regulation, Neoplastic/genetics
  • Humans
  • Neoplasms/genetics
  • Phosphorylation
  • Proto-Oncogene Proteins B-raf/metabolism
  • RNA, Long Noncoding/genetics
  • Ribosomal Protein S6 Kinases, 90-kDa/metabolism
  • Y-Box-Binding Protein 1/metabolism

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