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NR1D1 regulation by Ran GTPase via miR4472 identifies an essential vulnerability linked to aneuploidy in ovarian

Zied Boudhraa1,2, Kossay Zaoui1,2, Hubert Fleury1,2

  • 1Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.

Oncogene
|November 7, 2021
PubMed

Insights

Targeting Ran in epithelial ovarian cancer (EOC) exploits vulnerabilities created by aneuploidy. Inhibiting Ran, via the Ran/NR1D1 axis, offers a synthetic lethal strategy for treating aneuploid cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Aneuploidy, a hallmark of cancer, also presents unique vulnerabilities.
  • Epithelial ovarian cancer (EOC) is frequently characterized by aneuploidy.
  • Understanding cancer-specific dependencies is crucial for targeted therapies.

Purpose of the Study:

  • To investigate the role of Ran in aneuploid EOC survival.
  • To explore the Ran/NR1D1 axis in DNA damage repair in aneuploid cells.
  • To identify a potential synthetic lethal strategy targeting aneuploid EOC.

Main Methods:

  • Induction of aneuploidy in diploid EOC cell lines and normal cells.
  • Analysis of the correlation between Ran and the tumor suppressor NR1D1.
  • Investigation of the mechanism involving miR4472, NR1D1, PARP1, and BRCA1.
  • Assessment of DNA damage accumulation and cell lethality upon Ran loss.

Main Results:

  • Aneuploid cells exhibit increased dependency on Ran.
  • An inverse correlation exists between Ran and NR1D1, crucial for DNA repair.
  • Ran, via miR4472, destabilizes NR1D1 mRNA, affecting DNA repair pathways.
  • Loss of Ran leads to NR1D1 induction, DNA damage, and cell death in aneuploid EOC.

Conclusions:

  • Ran inhibition is a viable strategy targeting aneuploid EOC.
  • The Ran/NR1D1 axis plays a critical role in repairing DNA damage in aneuploid cells.
  • Exploiting aneuploidy-dependent vulnerabilities offers a promising synthetic lethal approach for EOC treatment.

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