Loss of miR-200c-3p promotes resistance to radiation therapy via the DNA repair pathway in prostate cancer
Radiotherapy represents a major curative treatment for prostate cancer (PCa), but some patients will develop radioresistance (RR) and relapse. The underlying mechanisms remain poorly understood, and miRNAs might be key players in the acquisition and maintenance of RR. Through their encapsulation in small extracellular vesicles (EVs), they can also be relevant biomarkers of radiation response. Using next-generation sequencing, we found that miR-200c-3p was downregulated in PCa RR cells and in their small EVs due to a gain of methylation on its promoter during RR acquisition. We next showed that its exogenous overexpression restores the radiosensitivity of RR cells by delaying DNA repair through the targeting of HP1α. Interestingly, we also observed downregulation of miR-200c-3p expression by DNA methylation in radiation-resistant lung and breast cancer cell lines. In summary, our study demonstrates that the downregulation of miR-200c-3p expression in PCa cells and in their small EVs could help distinguish radioresistant from sensitive tumor cells. This miRNA targets HP1α to delay DNA repair and promote cell death.
Authors
- Jean‐François Fonteneau (ORCID: https://orcid.org/0000-0002-3284-8319)
- Sophie Deshayes
- Christophe Blanquart (ORCID: https://orcid.org/0000-0002-0917-3747)
- Stéphane Supiot (ORCID: https://orcid.org/0000-0003-2094-1708)
- Laurence de Beaurepaire (ORCID: https://orcid.org/0000-0001-5150-5410)
- Maureen Labbé (ORCID: https://orcid.org/0000-0002-1495-4150)
- Vincent Potiron
- Benjamin Saintpierre
- Delphine Fradin (ORCID: https://orcid.org/0000-0001-6231-2649)
- Joëlle Véziers (ORCID: https://orcid.org/0000-0002-2182-5103)
- Marine Cotinat
- Franck Letourneur
- Manon Chang
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR)
- Institut de Cancérologie de l'Ouest (FR)
- Institut Cochin (FR)
- Oniris (FR)
- Unité en Sciences Biologiques et Biotechnologies de Nantes (FR)
- Université d'Angers (FR)
- Nantes Université (FR)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1038/s41419-024-07133-3
- Citations
- 13
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- Sunnybrook Research Institute
- Institut National de la Santé et de la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer