The HDAC inhibitor romidepsin renders liver cancer vulnerable to RTK targeting and immunologically active

Celia Sequera (), Margherita Grattarola, Floriane Cannet, Aurélie Dobric, Paula Michea Veloso, Melissa Methia, Sylvie Richelme, Abdessamad El Kaoutari, Paraskevi Kousteridou, Delphine Debayle, Lukas Kübler, Sandro Nuciforo, Yannick Boursier, Mathieu Dupont, Stefania Pizzimenti, Giuseppina Barrera, Jean-William Dupuy, Frédéric Saltel, Markus H. Heim, Sophie Vasseur, Xavier Adhoute, Fabienne Guillaumond, Jean-Paul Borg, Christian Morel and Flavio Maina ()
Additional contact information
Celia Sequera: Centre de Recherche en Cancérologie de Marseille (CRCM)
Margherita Grattarola: Centre de Recherche en Cancérologie de Marseille (CRCM)
Floriane Cannet: Centre de Recherche en Cancérologie de Marseille (CRCM)
Aurélie Dobric: Centre de Recherche en Cancérologie de Marseille (CRCM)
Paula Michea Veloso: Centre de Recherche en Cancérologie de Marseille (CRCM)
Melissa Methia: Centre de Recherche en Cancérologie de Marseille (CRCM)
Sylvie Richelme: Turing Center for Living Systems
Abdessamad El Kaoutari: Centre de Recherche en Cancérologie de Marseille (CRCM)
Paraskevi Kousteridou: Centre de Recherche en Cancérologie de Marseille (CRCM)
Delphine Debayle: Plateforme d’analyse des biomolécules PAB-Azur
Lukas Kübler: University of Basel
Sandro Nuciforo: University of Basel
Yannick Boursier: CPPM
Mathieu Dupont: CPPM
Stefania Pizzimenti: University of Turin
Giuseppina Barrera: University of Turin
Jean-William Dupuy: Plateforme Protéome
Frédéric Saltel: BoRdeaux Institute in onCology
Markus H. Heim: University of Basel
Sophie Vasseur: Centre de Recherche en Cancérologie de Marseille (CRCM)
Xavier Adhoute: Hôpital Saint-Joseph
Fabienne Guillaumond: Centre de Recherche en Cancérologie de Marseille (CRCM)
Jean-Paul Borg: Centre de Recherche en Cancérologie de Marseille (CRCM)
Christian Morel: CPPM
Flavio Maina: Centre de Recherche en Cancérologie de Marseille (CRCM)

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: Abstract 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-R26Met 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.

Date: 2025
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DOI: 10.1038/s41467-025-62934-0

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