HDAC Inhibitors Potentiate Doxorubicin Cytotoxicity in HepG2 Cells and Alter DNA-Repair- and p53-Associated Transcriptional Programs
- 1Department of Translational Genomics, GROW—Research Institute for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
Abstract
Histone deacetylase inhibitors (HDACis) can enhance responses to DNA-damaging chemotherapy, but how they alter doxorubicin (DOX)-induced transcriptional programs remains incompletely understood. We investigated the effects of valproic acid (VPA) and vorinostat (SAHA) on DOX cytotoxicity and associated molecular responses in HepG2 cells. HDAC inhibition, cell viability, apoptosis, and DOX IC50 values were assessed using histone H3 acetylation, cell counting, Alamar Blue assays, and cleaved caspase-3 immunofluorescence. Transcriptomic responses were analyzed by RNA sequencing, differential expression analysis, and Hallmark gene set enrichment analysis, with selected findings evaluated by RT-qPCR, Western blotting, and comparison with published CRISPR/Cas9 DOX-response data. Both HDAC inhibitors increased histone H3 acetylation and enhanced DOX cytotoxicity, markedly reducing DOX IC50 values. VPA co-treatment also increased DOX-induced cleaved caspase-3 signaling. RNA-seq showed broad transcriptional remodeling, including depletion of the DNA-repair gene set following VPA treatment and attenuation of canonical p53-responsive genes during HDACi–DOX co-treatment. Several HDACi-repressed DNA-repair genes overlapped with genes whose loss sensitized cells to DOX in a published CRISPR screen. HDAC inhibition therefore enhances DOX cytotoxicity and is accompanied by alterations in DNA-repair-associated and p53-responsive transcriptional programs.
Related
- KPB82 potently and selectively inhibits ACER2 and protects tumor and primary cells from doxorubicin-induced cytotoxicity
- 5-azacytosine induces cytotoxicity via 5-methylcytosine depletion on chromatin-associated RNA in leukemia
- A Common Small-Molecule Inhibitor Targeting Multiple Siglecs Associated with Immune Checkpoint Suppression of Cytotoxicity and Phagocytosis.
- Dynamic merging of enhancer- and promoter-associated assemblies is coupled to transcriptional bursting
- Stage-specific transcriptional atlas of goose satellite cells uncovers sex-biased molecular dynamics associated with embryonic skeletal muscle development
BibTeX
@article{guo2026hdac,
title = {{HDAC Inhibitors Potentiate Doxorubicin Cytotoxicity in HepG2 Cells and Alter DNA-Repair- and p53-Associated Transcriptional Programs}},
author = {Kaidi Guo and Marcel van Herwijnen and Florian Caiment and Twan van den Beucken},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209091},
url = {https://www.mdpi.com/1422-0067/27/20/9091},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - HDAC Inhibitors Potentiate Doxorubicin Cytotoxicity in HepG2 Cells and Alter DNA-Repair- and p53-Associated Transcriptional Programs
AU - Kaidi Guo
AU - Marcel van Herwijnen
AU - Florian Caiment
AU - Twan van den Beucken
PY - 2026
DA - 2026/10/14
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209091
UR - https://www.mdpi.com/1422-0067/27/20/9091
AB - Histone deacetylase inhibitors (HDACis) can enhance responses to DNA-damaging chemotherapy, but how they alter doxorubicin (DOX)-induced transcriptional programs remains incompletely understood. We investigated the effects of valproic acid (VPA) and vorinostat (SAHA) on DOX cytotoxicity and associated molecular responses in HepG2 cells. HDAC inhibition, cell viability, apoptosis, and DOX IC50 values were assessed using histone H3 acetylation, cell counting, Alamar Blue assays, and cleaved caspase-3 immunofluorescence. Transcriptomic responses were analyzed by RNA sequencing, differential expression analysis, and Hallmark gene set enrichment analysis, with selected findings evaluated by RT-qPCR, Western blotting, and comparison with published CRISPR/Cas9 DOX-response data. Both HDAC inhibitors increased histone H3 acetylation and enhanced DOX cytotoxicity, markedly reducing DOX IC50 values. VPA co-treatment also increased DOX-induced cleaved caspase-3 signaling. RNA-seq showed broad transcriptional remodeling, including depletion of the DNA-repair gene set following VPA treatment and attenuation of canonical p53-responsive genes during HDACi–DOX co-treatment. Several HDACi-repressed DNA-repair genes overlapped with genes whose loss sensitized cells to DOX in a published CRISPR screen. HDAC inhibition therefore enhances DOX cytotoxicity and is accompanied by alterations in DNA-repair-associated and p53-responsive transcriptional programs.
SN - 1422-0067
ER -