The histone deacetylase inhibitor romidepsin sensitizes HCC to receptor tyrosine kinase inhibitors in vitro and in vivo.

ABSTRACT: Background & Aims: Histone deacetylases (HDACs) are among the most common epigenetic dysregulations found in cancer, and considered as key events in tumour development and progression. Here we explored the therapeutic effects of romidepsin, a class-I HDAC inhibitor (HDACi), alone and in combination with receptor tyrosine kinase inhibitors (RTKi) in hepatocellular carcinoma (HCC). Methods: We bioinformatically evaluated class-I HDACs relevance in HCC patients through available datasets. Effects of romidepsin were assessed in HCC cell and mouse models. Molecular alterations were determined using proteomics, biochemistry, metabolic assays, immunostaining. The proteomic analysis was performed on Huh7 human HCC cell line non-treated or treated with romidepsin, cabozantinib or their combination, for 24h. Results: We report that overexpression of HDAC1 and HDAC2 occurs in HCC patients across five cohorts, and is correlated with decreased overall survival. We found that their targeting by romidepsin in HCC cell lines affects levels of several signals involved in cell cycle/survival and confers RTKi responsiveness. Mechanistically, romidepsin perturbs lipid metabolism, reduces cholesterol levels and upregulates fatty acid modulators. Furthermore, romidepsin affects the mitotic spindle machinery, leading to monopolar spindle formation, altered chromosome segregation, and cell blockage into mitosis illustrated by an accumulation of phospho-histone H3 positive HCC cells. Combined treatment of HCC cells with romidepsin plus cabozantinib (RomiCabo) switches a cytostatic effect, by romidepsin alone, into cell death by apoptosis. In vivo, RomiCabo induces regression of a subset of spontaneous preneoplastic as well as advanced lesions in the Alb-R26Met model faithfully recapitulating HCC resistance and heterogeneity. We characterize the upregulation of HR23B, a biomarker for tumour sensitivity to HDAC inhibition, and downregulation of the HCC marker AFP in RomiCabo treated Alb-R26Met tumours. Conclusions: Our findings provide the rationale of using romidepsin to exacerbate the vulnerability of HCC to RTKi for the treatment of patient subgroups.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Liver

DISEASE(S): Hepatocellular Carcinoma

SUBMITTER: Dupuy Jean-William  

LAB HEAD: Flavio Maina

PROVIDER: PXD041166 | Pride | 2025-08-04

REPOSITORIES: Pride