Sodium butyrate-mediated HDAC inhibition under hypoxic conditions modulates redox balance and tumor cell behavior in MCF-7 human breast cancer cells
Abstract
Hypoxia and epigenetic dysregulation are key contributors to breast cancer progression and therapeutic resistance. However, the interaction between histone deacetylase (HDAC) inhibition and hypoxia-associated signaling remains incompletely understood. This study therefore aimed to evaluate the combined effects of sodium butyrate (NaBu), an HDAC inhibitor, and cobalt chloride (CoCl ₂ ), a chemical hypoxia-mimetic agent, on the biological behavior of MCF-7 breast cancer cells. To do this, cells were treated with NaBu, CoCl ₂ , or their combination. Cell viability, proliferation, intracellular reactive oxygen species (ROS) generation, and cell-cycle distribution were assessed using MTT, cell counting, NBT, and flow cytometry, respectively. Quantitative real-time PCR was also performed to evaluate the expression of HDAC1 , HIF-1α , c-MET , and lncRNA-H19 . NaBu reduced cell viability and proliferation in a dose- and time-dependent manner, accompanied by increased ROS generation and HDAC1 downregulation. CoCl ₂ induced a hypoxia-mimetic response characterized by HIF-1α and lncRNA-H19 upregulation and G2/Marrest, whereas prolonged or higher-dose exposure promoted ROS accumulation and growth inhibition. Combined treatment further reduced cell viability and proliferation, enhanced ROS accumulation, and modulated hypoxia-related gene expression compared with either treatment alone. Although G2/M arrest was also observed following combined treatment, the cell-cycle profile largely resembled that induced by CoCl ₂ alone, suggesting that hypoxia-mimetic signaling predominantly drove this response. Overall, HDAC inhibition enhanced the cellular response to hypoxia-mimetic stress, highlighting the therapeutic potential of integrating epigenetic modulation with hypoxia-targeting strategies. Nevertheless, further mechanistic, drug-interaction, and in vivo studies are required to validate these findings.
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BibTeX
@article{yari2026sodium,
title = {{Sodium butyrate-mediated HDAC inhibition under hypoxic conditions modulates redox balance and tumor cell behavior in MCF-7 human breast cancer cells}},
author = {Hadis Yari and Sajjad Sisakhtnezhad and Ali Bidmeshkipour},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-73344-7},
url = {https://www.nature.com/articles/s41598-026-73344-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sodium butyrate-mediated HDAC inhibition under hypoxic conditions modulates redox balance and tumor cell behavior in MCF-7 human breast cancer cells
AU - Hadis Yari
AU - Sajjad Sisakhtnezhad
AU - Ali Bidmeshkipour
PY - 2026
DA - 2026/10/07
JO - Scientific Reports
DO - 10.1038/s41598-026-73344-7
UR - https://www.nature.com/articles/s41598-026-73344-7
AB - Hypoxia and epigenetic dysregulation are key contributors to breast cancer progression and therapeutic resistance. However, the interaction between histone deacetylase (HDAC) inhibition and hypoxia-associated signaling remains incompletely understood. This study therefore aimed to evaluate the combined effects of sodium butyrate (NaBu), an HDAC inhibitor, and cobalt chloride (CoCl ₂ ), a chemical hypoxia-mimetic agent, on the biological behavior of MCF-7 breast cancer cells. To do this, cells were treated with NaBu, CoCl ₂ , or their combination. Cell viability, proliferation, intracellular reactive oxygen species (ROS) generation, and cell-cycle distribution were assessed using MTT, cell counting, NBT, and flow cytometry, respectively. Quantitative real-time PCR was also performed to evaluate the expression of HDAC1 , HIF-1α , c-MET , and lncRNA-H19 . NaBu reduced cell viability and proliferation in a dose- and time-dependent manner, accompanied by increased ROS generation and HDAC1 downregulation. CoCl ₂ induced a hypoxia-mimetic response characterized by HIF-1α and lncRNA-H19 upregulation and G2/Marrest, whereas prolonged or higher-dose exposure promoted ROS accumulation and growth inhibition. Combined treatment further reduced cell viability and proliferation, enhanced ROS accumulation, and modulated hypoxia-related gene expression compared with either treatment alone. Although G2/M arrest was also observed following combined treatment, the cell-cycle profile largely resembled that induced by CoCl ₂ alone, suggesting that hypoxia-mimetic signaling predominantly drove this response. Overall, HDAC inhibition enhanced the cellular response to hypoxia-mimetic stress, highlighting the therapeutic potential of integrating epigenetic modulation with hypoxia-targeting strategies. Nevertheless, further mechanistic, drug-interaction, and in vivo studies are required to validate these findings.
SN - 2045-2322
ER -