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LncRNA-OIS1 regulates DPP4 activation to modulate senescence induced by RAS

Li Li1, Pieter C van Breugel1, Fabricio Loayza-Puch1

  • 1Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.

Nucleic Acids Research
|February 27, 2018
PubMed

Insights

Oncogene-induced senescence (OIS) is a tumor suppressor mechanism. Researchers identified lncRNA-OIS1 as crucial for OIS, linking it to the tumor suppressor DPP4 activation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Oncogene-induced senescence (OIS) acts as a tumor suppressor mechanism.
  • Long non-coding RNAs (lncRNAs) are increasingly recognized for their roles in cancer, exhibiting both oncogenic and tumor-suppressive functions.
  • Dysregulated lncRNA expression is linked to tumorigenesis and metastasis.

Purpose of the Study:

  • To identify long non-coding RNAs (lncRNAs) involved in oncogene-induced senescence (OIS).
  • To investigate the function of a specific lncRNA, lncRNA-OIS1, in the OIS pathway.
  • To elucidate the relationship between lncRNA-OIS1, OIS, and tumor suppressor genes.

Main Methods:

  • Differential expression analysis of lncRNAs in senescent versus non-senescent human fibroblast cells.
  • Loss-of-function screen using RNA interference (RNAi) to assess the role of differentially expressed lncRNAs in OIS.
  • Subcellular localization studies of lncRNA-OIS1.
  • Analysis of the impact of lncRNA-OIS1 manipulation on cell cycle regulators (e.g., CDKN1A) and nearby genes (e.g., DPP4).

Main Results:

  • lncRNA-OIS1 was identified as essential for OIS.
  • Knockdown of lncRNA-OIS1 led to senescence bypass, increased proliferation, reduced CDKN1A, and elevated cell-cycle gene expression.
  • lncRNA-OIS1 localizes to both the nucleus and cytoplasm.
  • Silencing lncRNA-OIS1 impaired the induction of the tumor suppressor Dipeptidyl Peptidase 4 (DPP4) during senescence.
  • Silencing DPP4 phenocopied lncRNA-OIS1 knockdown, and DPP4 re-expression rescued the senescence defect in lncRNA-OIS1-depleted cells.

Conclusions:

  • lncRNA-OIS1 is a critical regulator required for oncogene-induced senescence.
  • lncRNA-OIS1 functions by promoting the activation of the tumor suppressor DPP4.
  • This study reveals a novel link between lncRNA-OIS1 and DPP4 in the context of OIS and tumor suppression.

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