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

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

doi:10.1038/s41467-021-22746-4

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.

Highlights

Oncogene-induced senescence provides a barrier against malignant transformation
BRAF induction MIR31HG is upregulated and translocates to the cytoplasm where we show that it regulates the expression of a part of the senescence associated secretory phenotype (SASP) repertoire
We performed RNA sequencing in control cells and BRAF-induced senescent cells transfected with control siRNA or siRNA targeting MIR31HG

Summary

Introduction

Oncogene-induced senescence provides a barrier against malignant transformation. it can promote cancer through the secretion of a plethora of factors released by senescent cells, called the senescence associated secretory phenotype (SASP). The long non-coding RNA (lncRNA) TERRA has been shown to be a component of inflammatory exosomes and to modulate transcription of inflammatory cytokines in recipient cells[23] and other lncRNAs have been reported to regulate nuclear factor κB (NF-κB) activation and its downstream target genes[24,25,26]. These findings raise the hypothesis that lncRNAs could act as key players in the SASP induction during senescence. We show that MIR31HG promotes the interaction between YBX1 and the RSK kinase resulting in YBX1 phosphorylation and subsequent induction of IL1A translation

Methods

Results

Conclusion