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

Zied Boudhraa,Maxime Cahuzac,Anne-Marie Mes-Masson,Euridice Carmona,Guergana Tchakarska,Sophie Gilbert,Diane Provencher,Hubert Fleury,Jennifer Kendall-Dupont,Kossay Zaoui

doi:10.1038/s41388-021-02082-z

Abstract

While aneuploidy is a main enabling characteristic of cancers, it also creates specific vulnerabilities. Here we demonstrate that Ran inhibition targets epithelial ovarian cancer (EOC) survival through its characteristic aneuploidy. We show that induction of aneuploidy in rare diploid EOC cell lines or normal cells renders them highly dependent on Ran. We also establish an inverse correlation between Ran and the tumor suppressor NR1D1 and reveal the critical role of Ran/NR1D1 axis in aneuploidy-associated endogenous DNA damage repair. Mechanistically, we show that Ran, through the maturation of miR4472, destabilizes the mRNA of NR1D1 impacting several DNA repair pathways. We showed that NR1D1 interacts with both PARP1 and BRCA1 leading to the inhibition of DNA repair. Concordantly, loss of Ran was associated with NR1D1 induction, accumulation of DNA damages, and lethality of aneuploid EOC cells. Our findings suggest a synthetic lethal strategy targeting aneuploid cells based on their dependency to Ran.

Highlights

Ovarian cancer is the most lethal gynecologic malignancy in North America, with a 5-year survival rate of 45% [1]
We demonstrated that NR1D1 was able to interact with both PARP1 and BRCA1 leading to the inhibition of their related DNA repair pathways
Ran activity relies on a specific guanine nucleotide exchange factor (GEF) that promotes the GTP loading of Ran [7]

Summary

Introduction

Ovarian cancer is the most lethal gynecologic malignancy in North America, with a 5-year survival rate of 45% [1]. The most common form is epithelial ovarian cancer (EOC) where ~60% of patients present with a high-grade serous carcinoma (HGSC) [2]. Extensive genome sequencing studies have revealed that HGSC presents extremely high intra-tumoral heterogeneity [3], which poses specific challenges for therapeutic strategies. Some cell populations may be drug-resistant (or become drugresistant), leading to patient relapse. Independent of their heterogeneity, these EOC cell populations have complex karyotypes and aneuploidy [3, 4]. A strategy that targets aneuploidy may provide a promising approach for treating EOC, including cases that are carboplatin resistant

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