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Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers
Marwa W Aljardali1,2, Kevin M Kremer1,2,3, Jessica E Parker1,2,3
1Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
Abstract:
Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA1/2 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target of PARP1. We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARPi as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi.
Significance:
Currently, there are no reliable biomarkers for response to PARPi outside of homologous recombination deficiency. Herein we present a unique potential biomarker, with clear functional understanding of the molecular mechanism by which DDX21 nucleolar localization can predict response to PARPi.
Insights
PARP inhibitors (PARPi) show efficacy beyond BRCA mutations. DDX21 nucleolar localization predicts PARPi response and survival in endometrial and ovarian cancers, offering a new biomarker for expanded therapeutic use.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective against cancers with DNA repair defects, like BRCA1/2 mutations, via synthetic lethality.
- Emerging evidence suggests PARPi efficacy extends to cancers without BRCA mutations, indicating alternative mechanisms of action.
- Previous research identified DDX21, an RNA helicase, as a PARP1 target involved in a PARPi mechanism in breast cancer.
Purpose of the Study:
- To investigate the role of DDX21, an RNA helicase, in endometrial and ovarian cancers treated with PARPi.
- To explore DDX21 nucleolar localization as a potential biomarker for PARPi response and patient survival.
- To elucidate the molecular mechanism linking PARP1, DDX21, and cancer cell growth inhibition by PARPi.
Main Methods:
- Investigated PARP1-mediated ADPRylation of DDX21 in endometrial and ovarian cancer cell lines.
- Utilized niraparib, a PARP inhibitor, to assess the impact on DDX21 localization and rDNA transcription.
- Analyzed patient samples to correlate DDX21 nucleolar localization with PARPi sensitivity (IC50) and patient survival outcomes.
Main Results:
- Inhibition of PARP1-DDX21 ADPRylation by niraparib caused DDX21 mislocalization, reduced rDNA transcription, and inhibited cancer cell growth.
- High PARP1 expression correlated with high DDX21 nucleolar localization in both cancer types.
- High nucleolar DDX21 levels were associated with lower sensitivity to niraparib and decreased patient survival in endometrial cancer.
Conclusions:
- DDX21 nucleolar localization serves as a potential prognostic factor and predictive biomarker for PARPi therapy in endometrial and ovarian cancers.
- The findings support expanding the use of PARPi to additional cancer types based on DDX21 biomarker status.
- Understanding the DDX21-PARP1 interaction provides mechanistic insight into PARPi action beyond synthetic lethality.
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