The HDAC inhibitor romidepsin renders liver cancer vulnerable to RTK targeting and immunologically active
Histone deacetylases (HDACs) are epigenetic regulators frequently altered in cancer. Here we report that overexpression of HDAC1/2 occurs in Hepatocellular Carcinoma (HCC) patients, correlating with poor prognosis. We show that romidepsin, a class-I HDAC inhibitor, elicits a combinatorial perturbation of distinct molecular processes in HCC cells, altering lipid composition, mitotic spindle machinery, and levels of cell cycle/survival signals. Collectively, these alterations lead HCC cells to a vulnerable state, conferring dependency to receptor tyrosine kinase (RTK) signalling support. The cytostatic effects of romidepsin alone is converted into cytotoxicity by the RTK inhibitor cabozantinib in HCC models. We document that romidepsin+cabozantibib confers an immune-stimulatory profile in Alb-R26<sup>Met</sup> mouse models, with direct effects on primary human dendritic cell maturation in vitro. Our findings put forward the intricate crosstalk between epigenetics, metabolism, and immune response in cancer. The broad action of romidepsin on distinct cellular functions highlights its therapeutic potential for HCC treatment.
Authors
- Paulo A. S. Veloso
- Jean‐Paul Borg (ORCID: https://orcid.org/0000-0001-8418-3382)
- Frédéric Saltel (ORCID: https://orcid.org/0000-0002-0724-9680)
- C. Morel (ORCID: https://orcid.org/0000-0001-5359-6504)
- Sylvie Richelme
- Paraskevi Kousteridou (ORCID: https://orcid.org/0000-0002-8284-034X)
- Markus H. Heim (ORCID: https://orcid.org/0000-0002-7523-4894)
- Yannick Boursier (ORCID: https://orcid.org/0000-0003-3235-5271)
- Flavio Maina (ORCID: https://orcid.org/0000-0001-6100-4695)
- Celia Sequera (ORCID: https://orcid.org/0000-0001-6409-3910)
- Abdessamad El Kaoutari (ORCID: https://orcid.org/0000-0003-2334-3121)
- Stefania Pizzimenti (ORCID: https://orcid.org/0000-0001-6937-8632)
- Aurélie Dobric
- Fabienne Guillaumond (ORCID: https://orcid.org/0000-0001-7456-7315)
- Sandro Nuciforo (ORCID: https://orcid.org/0000-0002-1863-1869)
- Margherita Grattarola (ORCID: https://orcid.org/0000-0003-4172-7866)
- Jean‐William Dupuy (ORCID: https://orcid.org/0000-0002-2448-4797)
- Xavier Adhoute (ORCID: https://orcid.org/0000-0001-5977-800X)
- Lukas Kübler
- Giuseppina Barrera (ORCID: https://orcid.org/0000-0002-8587-4166)
- Sophie Vasseur (ORCID: https://orcid.org/0000-0002-2339-8854)
- Delphine Debayle (ORCID: https://orcid.org/0000-0003-2807-9198)
- Mathieu Dupont (ORCID: https://orcid.org/0000-0001-5228-5608)
- Floriane Cannet
- Melissa Methia
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Inserm (FR)
- University of Basel (CH)
- Institut Universitaire de France (FR)
- Aix-Marseille Université (FR)
- University Hospital of Basel (CH)
- Hôpital Saint Joseph (FR)
- Institut de Biologie du Développement Marseille (FR)
- Centre de Recherche en Cancérologie de Marseille (FR)
- Living Systems (United States) (US)
- Digestive Care (United States) (US)
- Laboratoire des Biomolécules (FR)
- BoRdeaux Institute of onCology (FR)
- University of Turin (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-25
- DOI
- https://doi.org/10.1038/s41467-025-62934-0
- Citations
- 8
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- Association pour la Recherche sur le Cancer
- Institut National de la Santé et de la Recherche Médicale
- Fondation de France
- Canceropôle PACA
- Institut National Du Cancer
- Association Française pour l'Etude du Foie
- Groupement des Entreprises Françaises dans la lutte contre le Cancer